The FEBS Journal - 2019 - Hollville - Apoptotic Cell Death Regulation in Neurons

STATE-OF-THE-ART REVIEW
Apoptotic cell death regulation in neurons

Emilie Hollville1, Selena E. Romero1,2 and Mohanish Deshmukh1,2
1 Neuroscience Center, UNC Chapel Hill, NC, USA
2 Department of Cell Biology and Physiology, UNC Chapel Hill, NC, USA
Keywords Apoptosis plays a major role in shaping the developing nervous system
Apaf-1; apoptosis; Bcl-2; caspase; JNK; during embryogenesis as neuronal precursors differentiate to become post-
neurodegeneration; neuronal maturation;
mitotic neurons. However, once neurons are incorporated into functional
neurons; NPCs; XIAP
circuits and become mature, they greatly restrict their capacity to die via
Correspondence apoptosis, thus allowing the mature nervous system to persist in a healthy
E. Hollville and M. Deshmukh, and functional state throughout life. This robust restriction of the apop-
UNC Neuroscience Center, Mary Ellen totic pathway during neuronal differentiation and maturation is defined by
Jones Building, #5102, 116 Manning Drive, multiple unique mechanisms that function to more precisely control and
Chapel Hill, NC 27599-7250, USA restrict the intrinsic apoptotic pathway. However, while these mechanisms
Tel: +1 919 843 6005
are necessary for neuronal survival, mature neurons are still capable of
E-mails: hollville@unc.edu (EH) and
activating the apoptotic pathway in certain pathological contexts. In this
mohanish@med.unc.edu (MD)
review, we highlight key mechanisms governing the survival of post-mitotic
(Received 8 March 2019, revised 15 May neurons, while also detailing the physiological and pathological contexts in
2019, accepted 20 June 2019) which neurons are capable of overcoming this high apoptotic threshold.
doi:10.1111/febs.14970
Introduction
The homeostatic maintenance of most organs and tis- NPCs, as well as young post-mitotic neurons, must be
sues is ensured by a controlled balance of proliferation selectively removed to allow for the refinement of neu-
by cell division and elimination via programmed cell ronal connectivity and the establishment of a mature
death throughout the life of an organism. However, and functional network [1,2]. While apoptosis during
the nervous system differs from most organs as neu- nervous system development is critical, the threshold
ronal cell division and proliferation is primarily required to induce apoptosis becomes much greater
restricted to embryonic development. In utero, neural once the mature nervous system is established, result-
precursor cells (NPCs) are produced in excessive num- ing in markedly less neuronal cell death. Indeed,
bers and differentiate into post-mitotic neurons, which mature neurons strikingly restrict the apoptosis path-
then grow and extend their axons to innervate target way after development to ensure their long-term sur-
regions. Following this period of excessive prolifera- vival and maintenance throughout life [3]. These
tion, superfluous NPCs and neurons are selectively restrictions increase the thresholds of apoptosis sensi-
eliminated during a period of substantial cell death by tivity throughout neuronal differentiation and matura-
apoptosis. This elimination is important as unneeded tion. For simplicity, these thresholds can be considered
Abbreviations
ALS, amyotrophic lateral sclerosis; BIR, baculoviral IAP repeat; CGNs, cerebellar granule neurons; cyt c, cytochrome c; DUSP, dual
specificity phosphatase; ER, endoplasmic reticulum; ETC, electron transport chain; GSH, glutathione; IAP, inhibitor of apoptosis proteins;
JIP, JNK-interacting protein; JNK, c-Jun N-terminal kinase; MAPK, mitogen activated protein kinase; MLK, mixed-lineage kinase; MOMP,
mitochondrial outer membrane permeabilization; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin; NGF, nerve growth factor; NPCs, neural
precursor cells; PD, Parkinson’s disease; XIAP, X-linked inhibitor of apoptosis.
3276 The FEBS Journal 286 (2019) 3276–3298 ª 2019 Federation of European Biochemical Societies
17424658, 2019, 17, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.14970 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [30/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
E. Hollville et al. Neuronal apoptosis
to fall into three distinct developmental stages of increas- at the mitochondria. Others, known as BH3-only sen-
ing apoptotic restriction: (a) NPCs (mitotic); (b) young sitizers (e.g., Bad, Bmf, Hrk/DP5, Noxa) bind to and
neurons (post-mitotic and establishing neuronal connec- inhibit anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL, Bcl-
tions); and (c) mature neurons (post-mitotic and fully w, Mcl-1). Anti-apoptotic Bcl-2 proteins inhibit death
integrated in the neural network). As the mammalian either by directly binding to activated Bax and Bak or
neuronal apoptosis pathway has been best studied in by binding and sequestering the activator BH3-only
young neurons (e.g., neonatal sympathetic neurons, proteins [4–6]. Thus, depending on the specific cell type
embryonic dorsal root ganglion neurons, embryonic cor- and context, Bax and Bak activation requires either
tical neurons), this review will focus primarily on the the activator only, sensitizer only, or both types of
mechanisms by which the intrinsic apoptotic pathway is BH3-family proteins.
activated and regulated in young neurons. In particular, Once activated, Bax and Bak form oligomers that
we will discuss the unique aspects of apoptotic regulation insert in the mitochondrial outer membrane, forming
in neurons that are distinct from other cells. We also pores that result in Mitochondrial Outer Membrane
highlight some of the known differences in this pathway Permeabilization (MOMP). A consequence of MOMP
between NPCs and young neurons as well as some of the is the release of proteins from the mitochondrial inter-
mechanisms by which this pathway becomes further membrane space. These include cytochrome c (cyt c),
restricted as young neurons become mature. Smac/DIABLO, the protease Omi/HtrA2, the nuclease
EndoG, and the oxidoreductase AIF. In the cytosol,
cyt c binds to Apaf-1 leading to the formation of a
Overview of the mammalian intrinsic
platform known as the apoptosome, which is responsi-
apoptotic pathway
ble for the activation of an initiator caspase, Caspase-9
The intrinsic (also referred to as the mitochondrial) (Casp9). Activated Casp9 can then cleave and activate
apoptotic pathway can be engaged in response to a effector caspases such as Caspase-7 (Casp7) and Cas-
number of cellular stresses, but can typically be pase-3 (Casp3). These effector caspases are responsible
induced with stimuli such as tropic factor deprivation, for the cleavage of hundreds of cellular proteins. Smac/
DNA damage, or endoplasmic reticulum (ER) stress. DIABLO and Omi/HtrA2 are both involved in neutral-
While these stressors activate stimulus-specific signal- izing XIAP (X-linked inhibitor of apoptosis), a cytoso-
ing events (e.g., reduced Protein Kinase B/Akt signal- lic protein that inhibits caspases. Finally, proteins such
ing, activation of c-Jun N-terminal kinase by trophic as EndoG and AIF are known to translocate to the
factor deprivation, or activation of p53 with DNA nucleus to promote chromatin condensation and DNA
damage), they ultimately converge on the activation of fragmentation after their release from mitochondria.
pro-apoptotic Bcl-2 family proteins that control the Altogether, cellular apoptotic stimuli converge on the
integrity of mitochondrial membranes. The Bcl-2 pro- activation of BH3-family proteins to result in the
tein family is comprised of both pro-apoptotic (e.g., release of mitochondrial proteins that promote the
Bax, Bak) and anti-apoptotic (e.g., Bcl-2, Bcl-xL, Mcl- orchestrated dismantlement of cells [7].
1) members. Importantly, a subset of the pro-apoptotic
members of the Bcl-2 family, known as the BH3-only
Cell death controls in neurons: JNK
proteins, are sentinels of cellular stresses and their role
signaling pathway
is to activate the intracellular apoptotic pathway. In
mammals, the main pro-apoptotic BH3-only proteins
JNks in neuronal apoptosis
are Bim, Puma, Noxa, Hrk/Dp5, Bad, Bid and Bmf.
Death signaling can activate the BH3-only proteins by The c-Jun N-terminal kinases (JNKs, also known as
various mechanisms that include transcriptional induc- stress-activated protein kinases) belong to the family
tion (e.g., Bim, Hrk/DP5, Bmf, Puma, Noxa), cleavage of serine-threonine Mitogen Activated Protein Kinases
(e.g., Bid), or dephosphorylation (e.g., Bad). The pri- (MAPKs) and are important signaling effectors of neu-
mary function of the BH3-only proteins is to activate ronal death in response to a wide variety of stimuli.
the pro-apoptotic Bcl-2 family proteins and inactivate Ten splice variants of JNKs are known to be gener-
the anti-apoptotic Bcl-2 family proteins. Thus, some ated from three genes in the human genome: Jnk1,
BH3-only proteins known as direct activators (e.g., Jnk2, and Jnk3. All JNK isoforms can phosphorylate
Bim, Bid, Puma) directly interact with Bax to promote and activate members of the AP-1 transcription factors
its conformational change and insertion into mito- family, although the various isoforms diverge in their
chondrial membranes. These proteins can also interact substrate specificity [8]. While Jnk1 and Jnk2 are ubiq-
with and activate Bak, which is constitutively localized uitously expressed, Jnk3 expression is mainly restricted
The FEBS Journal 286 (2019) 3276–3298 ª 2019 Federation of European Biochemical Societies 3277
Neuronal apoptosis E. Hollville et al.
to the brain and testis, suggesting non-overlapping phosphorylation of multiple targets, much of the
function with JNK1 and JNK2. Given its expression research in the context of neuronal apoptosis has been
patterns, Jnk3 has received considerable attention in focused on its ability to transcriptionally activate the
the context of neuronal death. Indeed, activation of pro-apoptotic BH3-only genes. Up-regulation of these
JNK3 initiates neuronal death in response to physio- genes occurs through direct JNK-mediated activation of
logical stimuli such as nerve growth factor (NGF) transcription factors (e.g., ATF2, Elk-1, c-Jun). Specifi-
withdrawal [9] or p75NTR death receptor stimulation cally, for example, JNK activation results in the phos-
[10], as well as pathological insults including excitotox- phorylation of c-Jun on Ser63/73 [11,12,14,15,17,20],
icity [11], axotomy [12,13], ischemia [14], and in the the subsequent translocation of c-Jun to the nucleus
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin) and its transcription-mediated activation of the BH3-
[15] and 6-hydroxydopamine [13] models of Parkin- only genes. This c-Jun-mediated transcriptional induc-
son’s disease (PD). However, the other isoforms of tion of BH3-only genes has been well-examined in a
JNK, especially JNK2, likely also contribute to neu- number of contexts in vitro including NGF withdrawal
ronal death. For example, the genetic knockout of of sympathetic neurons or potassium deprivation of
JNK3 results in only partial protection from cell death cerebellar granule neurons (CGNs), where Hrk/Dp5,
after optic nerve crush in retinal ganglion neurons or Bim, Bmf and Puma are known to be upregulated in a
in response to MPTP and 6-hydroxydopamine in JNK-dependent manner [20–24]. In vivo, Bim induc-
dopaminergic neurons; increased neuroprotection is tion in response to JNK activation is also observed
observed in Jnk2/3 double knockout mice [15–17]. in response to ischemia, MPTP or axonal injury
The JNK signaling pathway plays an essential role [14,25,26]. Another BH3-only gene Puma, which is well
in activating the intrinsic apoptosis pathway in neu- known to be activated by p53 in response to genotoxic
rons (Fig. 1) [18,19]. While JNKs can induce the damage, is also directly activated via JNK and c-Jun
Fig. 1. The pro-apoptotic JNK pathway is strictly restricted in neurons. (A) MAPKs are activated by an evolutionary conserved signaling
pathway that is initiated by a MAPK kinase kinase (MKKK), which phosphorylates and activates a MAPK kinase (MKK), which then
phosphorylates and activates the MAPK (e.g., JNKs). Two MKKs are involved in JNKs activation: MKK4/MEK4/SEK1 and MKK7/MEK7.
Among the 14 MKKKs known to activate MKK4/MKK7, members of the MLK proteins (e.g., DLK, MLK2, MLK3) play a crucial role in
neuronal cell death. Components of this pathway are integrated within scaffold proteins which coordinate their activation and subcellular
distribution. Particularly, JNKs are activated within scaffold proteins of the JNK-interacting protein (JIP) family which include JIP1, JIP2, and
JIP3 (JSAP1/Syd). Both JIP1 and JIP3 have been associated with JNKs activation in the context of neuronal death. JNKs, particularly JNK3
isoforms, activate the intrinsic pathway through direct phosphorylation of pro- and anti-apoptotic Bcl2 family members or through
phosphorylation and activation of c-Jun which induces BH3-only proteins transcription. (B) Neuronal JNK signaling pathway is restricted by
(1) antagonism of JIP by Akt/PKB, (2) Phr1/Mycbp2-mediated proteasomal degradation of DLK and (3) dephosphorylation of JNKs by the
DUSP/MKP DUSP1 and DUSP16.
in cortical neuron cultures treated with amyloid b1–42 Akt pathway enhances JNK activity and neuronal sus-
[27]. Interestingly, JNKs can also phosphorylate and ceptibility to neurotoxic stress [32,42,54,55].
activate p53, on Ser15, and induce the transcription of Interestingly, the antagonistic action of Akt is not
its pro-apoptotic target genes (e.g., Puma, Bax) to limited to JNK activation alone. Akt also exerts its
mediate apoptosis in neurons [26–30]. anti-apoptotic function in neurons through repression
JNKs contribute to Bax activation through phos- of the FoxO transcription factors and inactivation of
phorylation of cytosolic targets as well. These include the BH3-only protein Bad [32,56–59]. Neuronal Akt is
the BH3-only proteins Bim and Bad and the anti- activated by pro-survival signals including neu-
apoptotic protein Bcl-2. JNK-mediated phosphoryla- rotrophic factors and IGF-1 (Insulin-like Growth Fac-
tion of Bim on Ser65 is observed upon NGF with- tor-1). PI3K-mediated Akt activation results in direct
drawal in sympathetic neurons [19]. This phosphorylation and cytoplasmic retention of the tran-
phosphorylation site promotes the interaction with the scription factors FoxO1 and FoxO3a [55,56,60–62],
prolyl isomerase Pin1 in neurons to stabilize Bim at thus preventing the transcriptional upregulation of the
the protein level [31]. Ischemic brain injury stimulates BH3-only proteins Bim and Puma [63,64]. Addition-
JNK-dependent phosphorylation of Bad on Ser128 to ally, neuronal Akt restricts the BH3-only protein Bad
promote Bad:Bcl-xL interaction and antagonize Bcl-xL through a mechanism involving direct phosphorylation
anti-apoptotic function [32]. Additionally, phosphory- of Bad that reduces Bad binding to Bcl-xL and
lation of neuronal Bcl-2 on Ser87 might participate in increases Bad interaction and sequestration by the 14-
the release of Bax from Bax:Bcl-2 complexes to 3-3 proteins [32,57–59]. Active suppression of Akt pro-
enhance cyt c release [33,34]. survival signaling, which occurs via its direct phospho-
rylation and inactivation by AMPK and Trib3, is
required for the apoptosis to proceed in response to
Restriction of JNks in neurons
neurotoxic stimuli [65–68].
As JNK activation can induce neuronal death by mul- An additional point of restriction of JNKs activa-
tiple mechanisms, it is not surprising that JNK activation in neurons is by the constitutive ubiquitination
tion is tightly regulated in neurons. One of these and degradation of DLK. Of the many MAPKKKs
mechanisms involves phosphatases of the DUSP (dual responsible for MAPKs activation, the mixed-lineage
specificity phosphatases)/MKP (MAPK phosphatases) kinase (MLK) proteins, DLK, MLK2 and MLK3
family. Two of these phosphatases, namely DUSP1/ have been shown to be sufficient to induce JNKs and
MKP-1 and DUSP16/MKP-7, have been shown to apoptosis in neurons [69], and also to be required for
dephosphorylate JNKs [35,36] and modulate neuronal activation of JNK and apoptosis in various physiologi-
death during development [37,38] and in response to cal and pathological stimuli in neurons [18,52,69–72].
several neuronal insults including exposure to polyglu- Conserved in mammals, flies, and worms, the pathway
tamine-expanded Huntingtin, stroke, excitotoxicity or controlling DLK levels involves the E3 ubiquitin ligase
neurotrophic factor withdrawal [37–41]. While degra- Phr1 which targets DLK for proteasome mediated
dation of DUSPs by the proteasome appears to facili- degradation [73–76]. This point of restriction is over-
tate JNKs activation [39,41], some stresses can also come in response to axonal injury or trophic factor
stimulate DUSP expression and restrict JNK activa- deprivation by the accumulation of DLK [74,75]. In
tion [37,38,40]. The exact mechanisms by which mammals, DLK stabilization involves direct phospho-
DUSPs are regulated to prevent or permit JNK activa- rylation of DLK by JNKs on Thr43 complemented by
tion in neurons is not completely understood. USP9X-mediated de-ubiquitination of DLK [75]. In
Another mechanism by which JNK activation is addition, in flies, DLK accumulation is associated with
restricted in healthy neurons is by the binding of JIP1 a decrease in Phr1 homolog expression in response to
by the PKB/Akt kinase [42]. JIP1 belongs to JNK-in- axon crush [74].
teracting protein (JIP) family, with all members being
predominantly expressed in the brain [43,44]. JIP fam-
Cell death controls in neurons: Bcl-2
ily proteins form scaffolds that facilitate JNKs activa-
family proteins
tion (Fig. 1). Specifically, JIP1 and JIP3 are required
for JNKs activation and neuronal death in response to
Pro-apoptotic Bcl-2 proteins
a wide range of neurotoxic insults [18,20,42,45–53]. In
healthy neurons, JIP1 is bound by the Akt kinase, lim- The Bcl-2 family proteins exhibit dynamic changes in
iting access of JIP1 scaffold to JNK and preventing expression as the embryonic developing brain, com-
JNK activation. As a consequence, inhibition of the prised primarily of the proliferating NPCs, becomes
fully differentiated into post-mitotic neurons (Fig. 2).

These changes are consistent with the observation
that the apoptotic pathway becomes increasingly
restricted with post-mitotic neuronal differentiation
and maturation [3,77–79]. One example of this is via
the restricted expression of the pro-apoptotic protein
Bak with post-mitotic neuronal differentiation [80,81].
While most mitotic cells, including NPCs, express
both pro-apoptotic Bax and Bak proteins, which
function redundantly to promote apoptosis [82], this
redundancy is restricted in post-mitotic neurons that
are solely dependent on Bax alone for apoptosis and
do not express Bak [83]. Indeed, genetic deletion of
Bax alone confers neuronal protection in response to
multiple stresses [83–87]. Levels of Bax also decrease
in the brain postnatally but are maintained at low
levels [77,81,88–91]. However, this point of restriction
can be reversed by re-expression of Bax in response
to certain [92] neurotoxic insult [63,85,86,93–96].
Interestingly, neurons express an alternatively spliced
form of Bak, termed N-Bak, which is characterized
by the presence of an additional exon and is trans-
lated into a shorter peptide that is structurally simi-
lar to a BH3-only protein [97]. As a consequence, N-
Bak interacts with anti-apoptotic Bcl-2 protein Bcl-
xL rather than Bax and induces apoptosis in a Bax-
dependent manner [98]. It should be noted however
that some studies have counterintuitively reported
Fig. 2. Neuronal Bcl2 family proteins are transcriptionally regulated
that N-Bak presents neuroprotective capacities
during neuronal differentiation. NPCs are equipped with pro-
[97,99]. apoptotic effectors Bax and Bak and a large panel of BH3-only
The evolutionary reason why neurons restrict Bak members for apoptosis, and are mainly dependent on Mcl-1 for
and not Bax is unclear. Interestingly, while Bax and survival. Conversely, post-mitotic neurons uniquely rely on Bax and
Bak appear to have similar capabilities to induce express a larger panel of anti-apoptotic Bcl-2 proteins comprised of
MOMP and release cyt c, there are important differ- Bcl-2, Bcl-xL and Bcl-w. Neurons also markedly downregulate most
BH3-only genes. However, in response to pro-apoptotic stimuli,
ences in their mechanisms of activation. Bax is cytoso-
they activate transcription factors including c-Jun, ATF2, p53,
lic and the formation of Bax pores is a 2-step process
FoxO, CHOP or Myb to transcriptionally upregulate the BH3-only
that requires the translocation of Bax to the mitochon- genes.
drial outer membrane and next its oligomerization. On
the other hand, Bak is present on the surface of mito-
chondria and its activation only requires its oligomer- example, the NPCs and early differentiating post-mi-
ization [100,101]. Thus, Bax activation is potentially totic cortical neurons are highly dependent on Mcl-1,
more tightly controlled and could even be reversed via an anti-apoptotic member of the Bcl-2 family proteins.
its retro-translocation to the cytosol by Bcl-xL [102]. Not only is Mcl-1 highly expressed throughout the
The lack of expression of full length Bak likely pro- developing cortex, but deletion of Mcl-1 results in
vides neurons with the ability to strictly control apop- widespread apoptosis [103,104]. However, not all neu-
tosis with regulation of Bax alone. ronal precursors are completely dependent on Mcl-1
for survival as deletion of Mcl-1 in CGN precursors
does not result in increased apoptosis [105]. Mcl-1
Anti-apoptotic Bcl-2 proteins
expression is reduced in the adult brain [77] and dele-
The changes in the expression of the antiapoptotic tion of Mcl-1 in post-mitotic neurons did not result in
Bcl-2 family proteins in the developing and mature spontaneous apoptosis, although these neurons were
brain is more nuanced and individual members appear more sensitive to DNA damage [103]. Interestingly,
to have distinct functions in different cell types. For NPCs in the subventricular zone in the adult brain
continue to express Mcl-1 and are dependent on Mcl-1 mature brain [118], suggesting that it may have a
for survival like as seen for NPCs in the developing unique function in the nervous system during that
brain [106]. A different expression pattern is seen with specific developmental period. Consistent with the
Bcl-xL, another anti-apoptotic member of the Bcl-2 observation that multiple BH3-only proteins are
family. Bcl-xL is expressed at low levels throughout redundantly induced during apoptosis, the combined
the developing brain but increases in neurons with deletion or inhibition of multiple BH3-only genes is
post-mitotic differentiation. Consistent with this pat- often needed to effectively block neuronal apoptosis
tern of expression, deletion of Bcl-xL does not induce [63,92,119–130]. However, other stimuli such as those
widespread apoptosis in the developing brain but induced by arsenite exposure to cortical neurons can
results in the death of post-mitotic neurons in selective trigger the upregulation of a more restricted set of
brain regions [104,107]. Bcl-2 is also widely expressed BH3-only where deletion of Puma alone can confer
throughout the developing and mature brain [108]. neuroprotection [131,132]. While some of the BH3-
However, unlike Mcl-1, loss of Bcl-2 does not result in only proteins are activated by post-translational mech-
widespread apoptosis in the developing brain. At the anisms such as Bid via its cleavage or Bad via its
later postnatal stages, Bcl-2 deficient mice exhibit pro- dephosphorylation, most others, such as Bim, Puma,
gressive, but partial, degeneration of facial and periph- Noxa, Hrk/DP5 and Bmf, are transcriptionally
eral neurons [109]. One reason for this degeneration induced by apoptotic stimuli. Since neuronal apoptosis
could be the accumulation of reactive oxygen species is known to be blocked with RNA and protein synthe-
(ROS) observed in the brains of the Bcl-2-deficient sis inhibitors [133–141], transcriptional induction of
mice, pointing to an additional important function of the BH3-only proteins is thought to be a key event
Bcl-2 in the regulation of oxidative stress pathways that enables neurons to undergo apoptosis.
[110]. In addition to Bcl-2 and Bcl-xL, the adult Several transcription factors participate in BH3-only
mature brain express high levels of the anti-apoptotic genes upregulation, sometimes in concert, in response
Bcl-w. Restricted during embryonic development, Bcl- to apoptotic stimuli (Fig. 2). For example, NGF depri-
w expression greatly increases postnatally in maturing vation transcriptionally activates Bim, Puma, Hrk/
post-mitotic neurons [111,112]. Although absence of DP5, and Bmf [21,23,117,142,143]. Activation of the
Bcl-w does not induce noticeable neuronal loss in the AP-1 transcription factor c-Jun by phosphorylation by
mature nervous system, it nonetheless sensitizes adult JNK results in Bim [14,27,119,123], Puma [24,27,144]
hippocampal neurons to seizure-induced apoptosis or Hrk/Dp5 [20–22,124,145] induction in response to
[113]. In addition, loss of Bcl-w results in sensory neu- multiple neurotoxic stimuli. Typically elicited following
ropathy in adults, an effect consistent with the local- DNA damage, the p53 signaling pathway, stimulates
ization of Bcl-w (and Bcl-xL) in axons of sensory Puma and Noxa [121,146,147] in neurons. Induction of
neurons and a protective role against axonal degenera- Puma by p53 has also been reported in the mature
tion [114,115]. Together, these reports show that while brain following seizures [148] or MPTP-induced neuro-
NPCs in the developing brain are acutely dependent toxicity [63], but also in vitro in response to NGF
for survival on Mcl-1 alone, this changes with post-mi- withdrawal [38] or amyloid b [149]. However, Puma is
totic differentiation with Bcl-2, Bcl-xL and Bcl-w play- frequently co-upregulated with Bim and their promot-
ing more important, but likely not completely ers have in common binding sites for several transcrip-
redundant, roles in neurons. tion factors including c-Jun [24,27,144], FoxO3a
[24,63] and CHOP [150,151]. The FoxO transcription
factors FoxO1 and FoxO3a are activated downstream
Pro-apoptotic BH3-only proteins
of AMPK [65,66], Trib3 [67,68], MST1 [64,152] or
The key Bcl-2 family proteins that control the initia- Cdk5/p35 [153] in response to stimuli such as NGF
tion of apoptosis are the pro-apoptotic BH3-only fam- withdrawal, oxidative stress or amyloid b to mediate
ily proteins. As would be anticipated, while many Bim induction. Typically, these kinases facilitate FoxO
BH3-only genes are expressed in the embryonic brain, nuclear translocation by relieving either Akt- or 14-3-
their expression is markedly reduced in neurons in the 3-mediated inhibition or sequestration of FoxO tran-
postnatal brain [81,91,116]. Interestingly, expression of scription factors. CHOP, a transcription factor upregu-
Hrk/DP5, a neuronal specific BH3-only gene [117], fol- lated in response to ER stress, is also capable of
lows a different pattern than the other BH3-only directly transactivating Bim and Puma promoters
genes: largely absent during embryonic development, [150,151,154]. Thus, ER stress may trigger Bim and
Hrk/DP5 expression is transiently induced at early Puma upregulation via cooperation between CHOP
postnatal stages and subsequently repressed in the and FoxO3a transcription factors in neurons [150,155].
Interestingly, another cyclin-dependent kinase, Cdk4, maturation and has been shown to be neuroprotective
which is able to induce E2F1-dependent transcriptional [173–175], suggesting that the remodeling of mitochon-
upregulation of B-Myb transcription factor, is also drial cristae is also in important event for cyt c release
required for Bim upregulation and neuronal death in neurons.
[156,157]. In many cell types, the permeabilization of mito-
Multiple mechanisms, both at the transcriptional chondria and release of cyt c is considered the ‘point-
and post-transcriptional level, repress BH3-only genes of-no-return’, after which cells are unable to recover
expression in neurons. Broadly speaking, the survival from the apoptotic stimuli [176,177]. Neurons, how-
pathways that repress the expression of BH3-only pro- ever, have an altered point of no return downstream
teins in healthy neurons are the PI3K/Akt and the of cyt c release. This altered point-of-no-return in neu-
MEK/ERK pathways. For example, neuronal Akt and rons has been best demonstrated in the context of
ERK5 repress FoxO3a transcription factor and sup- NGF deprivation induced apoptosis in sympathetic
pression of Akt or ERK5 is sufficient to promote Bim neurons. Interestingly, these neurons are able to fully
expression [56,65–68,158]. The pro-survival MEK- recover from apoptosis upon the re-addition of NGF,
ERK signaling pathway can also promote the protea- despite the complete release of cyt c from their mito-
somal degradation of Bim [159–162]. Phosphorylation chondria [178–180]. These results are further supported
of Bim on Ser65 by ERK1/2 leads to interaction with by microinjection studies where exogenous cyt c is
the ubiquitin ligase TRIM2, followed by polyubiquiti- injected into sympathetic neurons and other cell types
nation and proteasomal degradation of Bim. Consis- such as na€ıve PC12 cells. Importantly, cyt c injection
tent with this observation, TRIM2 is found to have a alone is not sufficient to induce apoptosis in neurons
neuroprotective function in response to precondition- but is sufficient to kill other cell types [178,181,182].
ing stress [163]. While Bad expression is also downreg- Likewise, directly inducing the release of endogenous
ulated in the maturing and adult brain via the ERK5 cyt c from mitochondria by overexpression of a BH3-
mediated phosphorylation of the transcription factor only protein alone is also not sufficient to trigger
CREB [158,164], its pro-apoptotic function is also con- apoptosis in sympathetic neurons, in the absence of
trolled by phosphorylation. Bad can be phosphory- other apoptotic stimuli [181]. Thus, in contrast to most
lated on several residues including Ser112, Ser136, other cell types, sympathetic neurons are not commit-
Ser155 and Ser170. Phosphorylation on Ser112 by the ted to die by the release of cyt c into the cytosol. How-
MEK/ERK/Rsk pathway [164–166] and on Ser136 by ever, other neurons may not be as capable of surviving
Akt [57] leads to its disassociation with Bcl-xL and complete MOMP. For example, overexpression of
increased interaction with the regulatory proteins 14-3- Puma is sufficient to induce apoptosis in embryonic
3 [58]. This phosphorylation-mediated sequestration of cortical neurons [183].
Bad with 14-3-3 permits Bcl-xL to effectively promote Instead of cyt c release, mitochondrial depolariza-
neuronal survival [32,59]. tion seems to constitute the point-of-no-return, as sym-
pathetic neurons remain fully recoverable between the
time they have released cyt c, but fail to recover after
Cell death controls in neurons:
the point at which they fully lose mitochondrial mem-
cytochrome c
brane potential [179,180]. In fact, in depth studies into
The most significant consequence of Bax activation via the mechanics of cyt c release and mitochondrial func-
the pro-apoptotic BH3-only proteins is the release of tion during apoptosis have shown that cyt c is released
cyt c, along with other mitochondrial proteins, into well before complete mitochondrial depolarization in
the cytosol. In addition to the formation of Bax pores neurons [180,184–186]. This then raises the question:
on the outer mitochondrial membrane, the release of how are neurons capable of maintaining their mito-
cyt c is enhanced by the remodeling of mitochondrial chondrial potential, even after pores have been formed
cristae [167]. In non-neuronal models, the OMA1 and to mediate release of cyt c? It is important to note that
YME1L proteases mediate the proteolysis of the dyna- the recoverability of the neurons requires that the
min-like GTPase OPA1 in response to mitochondrial apoptotic stimulus to be reversible, thus a majority of
depolarization to promote cristae remodeling [168– the studies described below use a model of NGF depri-
171]. Interestingly destabilization of the mitochondrial vation of sympathetic neurons.
electron transport chain (ETC) also seems to partici- It has been suggested that neurons that have initi-
pate in the release of cyt c [172]. Although the role of ated apoptosis in response to NGF withdrawal (in the
OMA1 and YME1L in neuronal apoptosis is not char- presence of a caspase inhibitor) do not rely on oxida-
acterized, Opa1 is upregulated with neuronal tive phosphorylation for the generation of ATP, but
are instead dependent on glycolysis [184]. By utilizing ligase Cul9/Parc [195]. Interestingly, whether or not cyt
glycolysis, these neurons are still capable of producing c is degraded seems to be dependent on the presence and
ATP even when the ETC is disrupted by the loss of availability of its binding protein Apaf-1. While cytoso-
cyt c. This ATP is not only important for regular cel- lic cyt c is not degraded in wild-type mouse embryonic
lular processes and keeping the cell alive, but it may fibroblasts, it is targeted for degradation in Apaf-1-defi-
also be important for maintaining the mitochondrial cient fibroblasts [195]. Thus, the degradation of cytoso-
membrane potential via a unique mechanism: running lic cyt c seen in neurons could be because neurons are
the ETC in reverse. NGF deprived neurons are cap- known to express low levels of Apaf-1 [196,197].
able of reversing the ETC, thus consuming ATP to
generate a proton gradient that will maintain the mito-
Cell death controls in neurons: Apaf-1
chondrial membrane potential for a short period [184].
However, this mechanism is not sustainable over long Apaf-1, the main scaffold protein of the apoptosome
periods of time and once the mitochondrial membrane complex, contains an N-terminal caspase recruitment
potential is lost, neurons can no longer be rescued with domain (CARD), nucleotide-binding oligomerization
NGF re-addition [180,187]. Though neurons are able domain (NOD), and 12–13 WD40 repeats on the C-
to significantly delay their apoptotic point–of-no-re- terminus [198,199]. Apaf-1 is kept in an auto-in-
turn to mitochondrial depolarization, they are still hibitory state by the WD40 domains, rendering it inca-
exposed to cytosolic cyt c, which in most cell types is a pable of forming the apoptosome. However, binding
potent trigger for caspase activation and apoptosis. of cyt c to Apaf-1 via the WD40 domain, disrupts the
How, then, are neurons able to survive cytosolic cyt c auto-inhibited conformation of Apaf-1, causing the
when other cell types cannot? There are likely many oligomerization of Apaf-1 and recruitment of pro-
different mechanisms that neurons utilize to overcome Casp9 to form the apoptosome, resulting in the activa-
the dangers of cytosolic cyt c. Here, we will highlight tion of Casp9, which then cleaves and activates Casp3.
two potential ways in which neurons appear to restrict While Apaf-1 levels are maintained high in mitotic
the apoptotic pathway after release of cyt c from the cells, its levels decrease with neuronal differentiation
mitochondria: cyt c redox state, and its degradation and are markedly low in young post-mitotic neurons
(Fig. 3). [116,196,197,200]. The reason why Apaf-1 levels signif-
While the importance of the oxidized and reduced icantly decrease as mitotic cells become differentiated
forms of mitochondrial cyt c in shuttling electrons in into post-mitotic neurons is that Apaf-1 is transcrip-
the ETC is well recognized, it has become clear that tionally regulated by the cell cycle transcription factor
the redox state of cytosolic cyt c is also important for E2F1 [201–203], which is active in mitotic, but not
its apoptotic function [188,189]. The oxidized form of post-mitotic cells. As such, mitotic cells (e.g., NPCs)
cyt c is a more potent activator of caspases than its maintain higher levels of Apaf-1 through E2F1-depen-
reduced forms [181]. Healthy neurons are highly gly- dent transcription, and as E2F1 is shut down with
colytic and flux of Glucose-6-phosphate through the post-mitotic differentiation and exit from cell cycle,
pentose phosphate pathway generates high levels of Apaf-1 levels become simultaneously reduced in neu-
glutathione (GSH) which helps maintain the neuronal rons (Fig. 3). In addition, as neurons mature, Apaf-1
intracellular environment in a reduced state. As a con- expression is completely shut down [196,201,204,205]
sequence, any cyt c released from the mitochondria of with the Apaf-1 promotor becoming epigenetically
healthy neurons remains in a reduced state and poten- silenced via methylation of histones [201].
tially inactivated and thus, incapable of activating cas- The low levels of Apaf-1 not only limits the amount
pases [181]. During apoptosis, an increase in ROS of apoptosome activation in young neurons but also
promotes a more oxidized cellular environment making enables very effective control of caspase activation by
neurons more permissive for cyt c-mediated activation the inhibitor of apoptosis proteins (IAPs, discussed in
of caspases [181,190–193]. Thus, GSH functions to the next section). Interestingly however, while neurons
inactivate cytosolic cyt c in healthy neurons. However, restrict Apaf-1 expression, the restriction can be
it is important to note that GSH inhibits apoptosis at reversed as Apaf-1 levels are found to be increased in
multiple points in neurons as it can also block the neurons in the context of injury and disease such as
release of cyt c from neuronal mitochondria [191,194]. DNA damage [200,206], traumatic brain injury [196],
In addition to inactivating the pro-apoptotic func- hypoxia [207], ALS (amyotrophic lateral sclerosis)
tions of cyt c by altering its redox state, neurons can also [208], PD and dementia with Lewy Bodies [209]. In
target cytosolic cyt c for degradation [195]. Degradation many of these situations, the increase in Apaf-1 is a
of cyt c is mediated, at least in part, by the E3 ubiquitin likely consequence of E2F1 upregulation as E2F1 and
Fig. 3. Multiple breaks are in place to restrict apoptosis beyond cyt c release in post-mitotic neurons. In post-mitotic neurons, reduced
release of cyt c is achieved through restricted Bax expression and suppression of Bak compared to NPCs. While reducing environment due
to increased GSH, as well as CUL9-mediated proteasomal degradation of cyt c confine the apoptosome formation, reduced expression of
effector caspases and an increased XIAP to Apaf-1 ratio are in place to limit caspase activity in post-mitotic neurons.
many cell cycle genes are also known to be upregu- affected during maturation, the significant downregula-
lated during neurodegeneration [210,211]. It is impor- tion of its adaptor Apaf-1 [196,197,205] further
tant to note that E2F1 is not the sole transcription restricts the activation of the effector caspases via the
factor for Apaf-1, as p53 can also transcriptionally apoptosome in the mature nervous system.
induce Apaf-1 expression after DNA damage [200]. Consistently, mature neurons become extremely
Exactly why the restriction of Apaf-1 is reversible in resistant to triggers that mimic neurodevelopmental
these situations in unclear, but it could be that the cell death such as neurotrophic factor withdrawal
presence of Apaf-1 may enable death to occur specifi- [90,219]. Aside from this context, mature neurons
cally by apoptosis, thus reducing the overall inflamma- remain able to die in response to stress or insult, some-
tion that may otherwise occur during neuronal injury times however this occurs more slowly such as
or disease situations. observed in response to axotomy in adult retinal gan-
glion cells compared to neonatal retina [220]. Caspases
have nonetheless been shown to be activated and
involved, at least in part, in response to multiple trig-
caspases
gers in mature neurons. For instance, caspase inhibi-
Caspases play a major role in neurodevelopmental cell tion partly reduces or delays cell death observed in
death [212]. However, their involvement in cell death response to neurotoxic insults such as potassium with-
of the mature nervous system is far less prominent. drawal in CGNs [221,222], excitotoxicity [223–225],
Reduced activation of effector Casp3 is observed in hypoxia-ischemia [226,227], axotomy or axonal injury
response to injury such as brain ischemia and axotomy [228–230], but also in models of neurodegenerative dis-
in adult compared to neonate rodents [213,214], eases including PD [231], Alzheimer’s disease [210] and
though mature neurons remain sensitive to insults and ALS [232].
engage both apoptotic and non-apoptotic pathways As previously mentioned, many of these triggers
[2]. Indeed, maturation of the nervous system is associ- require de novo protein synthesis to execute apoptosis.
ated with decreased expression of several caspase genes Indeed, caspases are often re-expressed in the mature
[215–217], including effector caspase-7 and caspase-3 nervous system in response to various apoptotic stim-
[205,215,218]. Interestingly, while Casp9 levels are not uli. Effector Casp3 is without a doubt the caspase
member that is the most reported to be upregulated at consistent with the observation that endogenous XIAP
the transcriptional level in response to neuronal insult. is important for restricting apoptosis, the XIAP-defi-
For example, increases in Casp3 mRNA is observed in cient mice exhibit increased neuronal loss in the con-
response to potassium withdrawal in CGNs [233], text of neuronal hypoxia-ischemia [263]. It is
brain ischemia [234], axotomy [214], mutant important to note that XIAP is not required for the
SOD1G93A [232] and brain injury [196]. However, survival of neurons under normal, non-stressed condi-
very little is known about the mechanisms leading to tions. Indeed, the XIAP-deficient mice do not exhibit
Casp3 upregulation. Analysis of the caspase-3 pro- any overt brain deficits [264]. However, the fact that
moter has revealed binding sites for several transcrip- reduction of XIAP makes neurons more susceptible in
tion factors including p53, E2F1 and AP-1 [235]. various stress-inducing contexts [248,259–263] indicates
While p53 does not seem to play a major role in Cap- that endogenous XIAP is an important ‘safety brake’
s3 expression in the nervous system [200], it has been in neurons that can restrict cell death in stress situa-
reported to mediate upregulation of Casp6 and Apaf-1 tions that may cause limited mitochondrial damage
[200,236]. The JNK pathway has also been implicated and the accidental release of cyt c (Fig. 3). The ability
in Casp3 re-expression in response to multiple neuro- of XIAP to strictly inhibit caspases in neurons is not
toxic insults [52,53,72,141]. For example, the JNK-reg- because of high XIAP levels but rather a direct conse-
ulated transcription factors c-Jun and ATF2 have been quence of restricted Apaf-1 expression in these post-
reported to stimulate caspase-3 expression in response mitotic cells. In neurons, the low levels of caspase acti-
to potassium deprivation in CGNs, [237]. vation resulting from the restricted apoptosome forma-
tion can be easily antagonized by XIAP [197]. This
contrasts from the situation in mitotic cells such as
NPCs, where high Apaf-1 levels trigger efficient activa-
inhibitor of apoptosis proteins
tion of caspases which can overwhelm the antiapop-
The IAP were first discovered in mammals through totic capability of XIAP.
homology studies which probed for proteins that con- Interestingly, XIAP has been found to be inactivated
tained the baculoviral IAP repeat (BIR) domains [238]. by different mechanisms in many situations that result
As the name suggests, the BIR domain was first dis- in neuronal death. For example, physiological triggers
covered in baculovirus, where it served to inhibit of apoptosis such as NGF deprivation of sympathetic
apoptosis [239]. However, while a large number of neurons cause a reduction in XIAP levels such that
BIR domain-containing proteins have been discovered apoptosis can proceed [262]. Decrease in XIAP levels
in mammalian cells (e.g., Survivin, Apollon/BRUCE, are also seen in other contexts of neuronal injury
KIAP/Livin, NAIP, cIAP1, cIAP2, XIAP), only a [260,261,265,266]. In the context of DNA damage,
small subset of those are shown to have antiapoptotic while XIAP levels remain stable, strong Apaf-1 induc-
activities [240–242]. These include cIAP1, cIAP2 and tion by p53 permits caspase activation because of effi-
XIAP, and even among these, XIAP has the most cient apoptosome engagement [206]. Additionally,
potent activity to inhibit apoptosis via it ability to XIAP can also be inhibited by posttranslational mech-
directly bind to and inhibit the apoptotic caspases anisms as in animal models of PD and PD patient
[243–245]. samples, XIAP was found to be inactivated by nitrosy-
X-linked inhibitor of apoptosis contains three BIR lation of the cysteine residues in the BIR domain
domains which allow it to directly bind and inhibit [267].
Casp3, Casp7, and Casp9 [243]. Indeed, overexpression
of XIAP is sufficient to prevent Casp3 activation and
Concluding remarks
neuronal cell death in vitro [246–248], but also follow-
ing axotomy [249], cerebral ischemia [250,251], hypoxia Important modulations of the apoptotic pathway
[252], and in models of PD [253,254], ALS [255,256], occur throughout neurodevelopment, from those
glaucoma [257], and retinitis pigmentosa [258]. Impor- accompanying NPCs differentiation to the changes
tantly, endogenous XIAP is also important in restrict- that occur as post-mitotic neurons become mature and
ing caspases and apoptosis in neurons as its reduction are incorporated into functional and refined circuits.
[248,259–261] or completely deficiency [262,263] makes The increased threshold for neuronal apoptosis is asso-
neurons more vulnerable to multiple apoptotic trig- ciated with restriction of the apoptotic machinery at
gers. In particular, the striking resistance of sympa- various levels including molecular, transcriptional and
thetic neurons to microinjection of cyt c, is because of metabolic repression of sensors and effectors of the
strict inhibition of caspases by XIAP [262]. Also, mitochondrial apoptotic pathway [3]. It would be
interesting to understand what are the signals and axonal outgrowth [276,277]. Using these apoptotic mole-
molecular mechanisms that initiate and drive this pro- cules in such a way requires tight control of the apop-
gressive switch toward a more restrictive state. For totic machinery as to not accidentally kill the neuron.
example in the case of the nervous system, decreased This is impressive considering that, in these contexts,
sensitivity to apoptosis coincides with the establish- neurons need to activate caspases with spatial precision.
ment of neuronal connectivity. Are these two processes Thus, analyzing the mechanisms allowing the mitochon-
interconnected? Are they tissue-specific or are there drial pathway to become activated in a very restricted
common reprogramming pathways in all post-mitotic fashion, as well as identifying the differences in its acti-
tissues? Interestingly, some of the mechanisms evoked vation in apoptotic versus non-apoptotic context, will
in this review have also been observed in other post- provide significant insight into neuronal survival and
mitotic systems including cardiomyocytes and myo- function in physiological and pathological situations.
tubes [77,262,268]. These findings suggest the existence
of potentially conserved developmental regulatory
Acknowledgements
pathways responsible for restricting the apoptotic
machinery in post-mitotic cells. Yet, some regulatory We thank Dr Matt Geden for insightful comments on
pathways have so far only been described in neurons this manuscript. This work was supported by a grant
(e.g., Phr1-mediated degradation DLK) and are most from National Institutes of Health (GM118331) to
likely under the control of neuronal maturation-associ- MD.
ated signals that are neuron-specific.
Restriction of the apoptotic machinery in the mature
Conflict of interest
nervous system is not necessarily associated with com-
plete shutdown of the apoptotic pathway. In fact, mul- The authors declare no conflict of interest.
tiple studies have shown how injury or pathological
conditions can activate the mitochondrial pathway
Author contributions
through overcoming the brakes on the apoptotic path-
way to successfully activate apoptosis. Consequently, EH and SER wrote the manuscript and MD helped
use of caspase inhibitors has proven somewhat success- edit the text.
ful in the case of acute neurological traumatic damage
in animal models [269]. Conversely, it has been more
References
challenging to understand how neuronal death occurs
in neurodegenerative situations. Though the apoptotic 1 Burek MJ & Oppenheim RW (1996) Programmed cell
pathway is often reactivated in neurodegenerative dis- death in the developing nervous system. Brain Pathol
eases, its contribution to the death observed in these 6, 427–446.
pathologies seems more limited and the field has been 2 Fricker M, Tolkovsky AM, Borutaite V, Coleman M
actively investigating which alternative non-apoptotic, & Brown GC (2018) Neuronal cell death. Physiol Rev
caspase-independent pathways could be involved. 98, 813–880.
Interestingly, studies are now focusing on the role of 3 Kole AJ, Annis RP & Deshmukh M (2013) Mature
several non-apoptotic pathways activated in response neurons: equipped for survival. Cell Death Dis 4, e689.
4 Shamas-Din A, Brahmbhatt H, Leber B & Andrews
to disease-associated or neurotoxic insults [270,271].
DW (2011) BH3-only proteins: orchestrators of
For example, calpains, another family of cysteine pro-
apoptosis. Biochim Biophys Acta 1813, 508–520.
teases, have been shown to promote caspase-indepen-
5 Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ &
dent cell death in neurons. In these situations, calpains
Green DR (2010) The BCL-2 family reunion. Mol Cell
may compete with caspases as calpains can cleave an
37, 299–310.
inactivate Casp9 and Casp3 [272–275]. Future work 6 Happo L, Strasser A & Cory S (2012) BH3-only
might inform us on how these other non-apoptotic proteins in apoptosis at a glance. J Cell Sci 125, 1081–
pathways are regulated during development and matu- 1087.
ration of the nervous system. 7 Taylor RC, Cullen SP & Martin SJ (2008) Apoptosis:
Over the recent years, multiple studies have high- controlled demolition at the cellular level. Nat Rev Mol
lighted how the nervous system utilizes the pro-apop- Cell Biol 9, 231–241.
totic machinery for non-apoptotic purposes. For 8 Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss
example, neurons activate caspases via the mitochon- HK, Derijard B & Davis RJ (1996) Selective
drial pathway for non-apoptotic neuron-specific pro- interaction of JNK protein kinase isoforms with
cesses such as axon pruning, synaptic plasticity, and transcription factors. EMBO J 15, 2760–2770.
9 Bruckner SR, Tammariello SP, Kuan CY, Flavell RA, potentiates BAX-dependent apoptosis. Neuron 38, 899–
Rakic P & Estus S (2001) JNK3 contributes to c-Jun 914.
activation and apoptosis but not oxidative stress in 20 Towers E, Gilley J, Randall R, Hughes R, Kristiansen
nerve growth factor-deprived sympathetic neurons. J M & Ham J (2009) The proapoptotic dp5 gene is a
Neurochem 78, 298–303. direct target of the MLK-JNK-c-Jun pathway in
10 Kenchappa RS, Tep C, Korade Z, Urra S, Bronfman sympathetic neurons. Nucleic Acids Res 37, 3044–
FC, Yoon SO & Carter BD (2010) p75 neurotrophin 3060.
receptor-mediated apoptosis in sympathetic neurons 21 Harris CA & Johnson EM Jr (2001) BH3-only Bcl-2
involves a biphasic activation of JNK and up- family members are coordinately regulated by the JNK
regulation of tumor necrosis factor-alpha-converting pathway and require Bax to induce apoptosis in
enzyme/ADAM17. J Biol Chem 285, 20358–20368. neurons. J Biol Chem 276, 37754–37760.
11 Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, 22 Ma C, Ying C, Yuan Z, Song B, Li D, Liu Y, Lai B,
Zheng TS, Davis RJ, Rakic P & Flavell RA (1997) Li W, Chen R, Ching YP et al. (2007) dp5/HRK is a
Absence of excitotoxicity-induced apoptosis in the c-Jun target gene and required for apoptosis induced
hippocampus of mice lacking the Jnk3 gene. Nature by potassium deprivation in cerebellar granule
389, 865–870. neurons. J Biol Chem 282, 30901–30909.
12 Keramaris E, Vanderluit JL, Bahadori M, Mousavi K, 23 Kristiansen M, Menghi F, Hughes R, Hubank M &
Davis RJ, Flavell R, Slack RS & Park DS (2005) c- Ham J (2011) Global analysis of gene expression in
Jun N-terminal kinase 3 deficiency protects neurons NGF-deprived sympathetic neurons identifies
from axotomy-induced death in vivo through molecular pathways associated with cell death. BMC
mechanisms independent of c-Jun phosphorylation. J Genom 12, 551.
Biol Chem 280, 1132–1141. 24 Ambacher KK, Pitzul KB, Karajgikar M, Hamilton
13 Brecht S, Kirchhof R, Chromik A, Willesen M, A, Ferguson SS & Cregan SP (2012) The JNK- and
Nicolaus T, Raivich G, Wessig J, Waetzig V, Goetz AKT/GSK3beta- signaling pathways converge to
M, Claussen M et al. (2005) Specific regulate Puma induction and neuronal apoptosis
pathophysiological functions of JNK isoforms in the induced by trophic factor deprivation. PLoS One 7,
brain. Eur J Neurosci 21, 363–377. e46885.
14 Kuan CY, Whitmarsh AJ, Yang DD, Liao G, 25 Harder JM, Fernandes KA & Libby RT (2012) The
Schloemer AJ, Dong C, Bao J, Banasiak KJ, Haddad Bcl-2 family member BIM has multiple glaucoma-
GG, Flavell RA et al. (2003) A critical role of neural- relevant functions in DBA/2J mice. Sci Rep 2, 530.
specific JNK3 for ischemic apoptosis. Proc Natl Acad 26 Perier C, Bove J, Wu DC, Dehay B, Choi DK,
Sci USA 100, 15184–15189. Jackson-Lewis V, Rathke-Hartlieb S, Bouillet P,
15 Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Strasser A, Schulz JB et al. (2007) Two molecular
Przedborski S, Rakic P & Flavell RA (2004) JNK- pathways initiate mitochondria-dependent
mediated induction of cyclooxygenase 2 is required for dopaminergic neurodegeneration in experimental
neurodegeneration in a mouse model of Parkinson’s Parkinson’s disease. Proc Natl Acad Sci USA 104,
disease. Proc Natl Acad Sci USA 101, 665–670. 8161–8166.
16 Ries V, Silva RM, Oo TF, Cheng HC, Rzhetskaya M, 27 Akhter R, Sanphui P, Das H, Saha P & Biswas SC
Kholodilov N, Flavell RA, Kuan CY, Rakic P & (2015) The regulation of p53 up-regulated modulator
Burke RE (2008) JNK2 and JNK3 combined are of apoptosis by JNK/c-Jun pathway in beta-amyloid-
essential for apoptosis in dopamine neurons of the induced neuron death. J Neurochem 134, 1091–1103.
substantia nigra, but are not required for axon 28 Fogarty MP, Downer EJ & Campbell V (2003) A role
degeneration. J Neurochem 107, 1578–1588. for c-Jun N-terminal kinase 1 (JNK1), but not JNK2,
17 Fernandes KA, Harder JM, Fornarola LB, Freeman in the beta-amyloid-mediated stabilization of protein
RS, Clark AF, Pang IH, John SW & Libby RT (2012) p53 and induction of the apoptotic cascade in cultured
JNK2 and JNK3 are major regulators of axonal cortical neurons. Biochem J 371, 789–798.
injury-induced retinal ganglion cell death. Neurobiol 29 Choi HJ, Kang KS, Fukui M & Zhu BT (2011)
Dis 46, 393–401. Critical role of the JNK-p53-GADD45alpha apoptotic
18 Ghosh AS, Wang B, Pozniak CD, Chen M, Watts RJ cascade in mediating oxidative cytotoxicity in
& Lewcock JW (2011) DLK induces developmental hippocampal neurons. Br J Pharmacol 162, 175–192.
neuronal degeneration via selective regulation of 30 Tamagno E, Parola M, Guglielmotto M, Santoro G,
proapoptotic JNK activity. J Cell Biol 194, 751–764. Bardini P, Marra L, Tabaton M & Danni O (2003)
19 Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu Multiple signaling events in amyloid beta-induced,
B, Alix S, Youle RJ, LaMarche A, Maroney AC et al. oxidative stress-dependent neuronal apoptosis. Free
(2003) JNK-mediated BIM phosphorylation Radic Biol Med 35, 45–58.
31 Becker EB & Bonni A (2006) Pin1 mediates neural- regulates a JNK scaffold during excitotoxic apoptosis.
specific activation of the mitochondrial apoptotic Neuron 35, 697–709.
machinery. Neuron 49, 655–662. 43 Kim IJ, Lee KW, Park BY, Lee JK, Park J, Choi IY,
32 Wang XT, Pei DS, Xu J, Guan QH, Sun YF, Liu XM Eom SJ, Chang TS, Kim MJ, Yeom YI et al. (1999)
& Zhang GY (2007) Opposing effects of Bad Molecular cloning of multiple splicing variants of JIP-
phosphorylation at two distinct sites by Akt1 and 1 preferentially expressed in brain. J Neurochem 72,
JNK1/2 on ischemic brain injury. Cell Signal 19, 1844– 1335–1343.
1856. 44 Kelkar N, Standen CL & Davis RJ (2005) Role of the
33 Guan QH, Pei DS, Zong YY, Xu TL & Zhang GY JIP4 scaffold protein in the regulation of mitogen-
(2006) Neuroprotection against ischemic brain injury activated protein kinase signaling pathways. Mol Cell
by a small peptide inhibitor of c-Jun N-terminal kinase Biol 25, 2733–2743.
(JNK) via nuclear and non-nuclear pathways. 45 Whitmarsh AJ, Kuan CY, Kennedy NJ, Kelkar N,
Neuroscience 139, 609–627. Haydar TF, Mordes JP, Appel M, Rossini AA, Jones
34 Pan J, Qian J, Zhang Y, Ma J, Wang G, Xiao Q, SN, Flavell RA et al. (2001) Requirement of the JIP1
Chen S & Ding J (2010) Small peptide inhibitor of scaffold protein for stress-induced JNK activation.
JNKs protects against MPTP-induced nigral Genes Dev 15, 2421–2432.
dopaminergic injury via inhibiting the JNK-signaling 46 Wang Z, Chen Y, Lu Y, Chen X, Cheng L, Mi X, Xu
pathway. Lab Invest 90, 156–167. X, Deng W, Zhang Y, Wang N et al. (2015) Effects of
35 Willoughby EA, Perkins GR, Collins MK & JIP3 on epileptic seizures: evidence from temporal lobe
Whitmarsh AJ (2003) The JNK-interacting protein-1 epilepsy patients, kainic-induced acute seizures and
scaffold protein targets MAPK phosphatase-7 to pentylenetetrazole-induced kindled seizures.
dephosphorylate JNK. J Biol Chem 278, 10731– Neuroscience 300, 314–324.
10736. 47 Im JY, Lee KW, Kim MH, Lee SH, Ha HY, Cho IH,
36 Jeanneteau F, Deinhardt K, Miyoshi G, Bennett AM Kim D, Yu MS, Kim JB, Lee JK et al. (2003)
& Chao MV (2010) The MAP kinase phosphatase Repression of phospho-JNK and infarct volume in
MKP-1 regulates BDNF-induced axon branching. Nat ischemic brain of JIP1-deficient mice. J Neurosci Res
Neurosci 13, 1373–1379. 74, 326–332.
37 Kristiansen M, Hughes R, Patel P, Jacques TS, Clark 48 Pan J, Pei DS, Yin XH, Hui L & Zhang GY (2006)
AR & Ham J (2010) Mkp1 is a c-Jun target gene that Involvement of oxidative stress in the rapid Akt1
antagonizes JNK-dependent apoptosis in sympathetic regulating a JNK scaffold during ischemia in rat
neurons. J Neurosci 30, 10820–10832. hippocampus. Neurosci Lett 392, 47–51.
38 Maor-Nof M, Romi E, Sar Shalom H, Ulisse V, 49 Repici M, Centeno C, Tomasi S, Forloni G, Bonny C,
Raanan C, Nof A, Leshkowitz D, Lang R & Yaron A Vercelli A & Borsello T (2007) Time-course of c-Jun
(2016) Axonal degeneration is regulated by a N-terminal kinase activation after cerebral ischemia
transcriptional program that coordinates expression of and effect of D-JNKI1 on c-Jun and caspase-3
pro- and anti-degenerative factors. Neuron 92, 991– activation. Neuroscience 150, 40–49.
1006. 50 Zhao J, Pei DS, Zhang QG & Zhang GY (2007)
39 Taylor DM, Moser R, Regulier E, Breuillaud L, Down-regulation Cdc42 attenuates neuronal apoptosis
Dixon M, Beesen AA, Elliston L, Silva Santos Mde F, through inhibiting MLK3/JNK3 cascade during
Kim J, Jones L et al. (2013) MAP kinase phosphatase ischemic reperfusion in rat hippocampus. Cell Signal
1 (MKP-1/DUSP1) is neuroprotective in Huntington’s 19, 831–843.
disease via additive effects of JNK and p38 inhibition. 51 Crocker SJ, Hayley SP, Smith PD, Mount MP, Lamba
J Neurosci 33, 2313–2325. WR, Callaghan SM, Slack RS & Park DS (2006)
40 Liu L, Doran S, Xu Y, Manwani B, Ritzel R, Regulation of axotomy-induced dopaminergic neuron
Benashski S, McCullough L & Li J (2014) Inhibition death and c-Jun phosphorylation by targeted
of mitogen-activated protein kinase phosphatase-1 inhibition of cdc42 or mixed lineage kinase. J
(MKP-1) increases experimental stroke injury. Exp Neurochem 96, 489–499.
Neurol 261, 404–411. 52 Itoh T, Horiuchi M, Ikeda RH Jr, Xu J, Bannerman
41 Choi BH, Hur EM, Lee JH, Jun DJ & Kim KT (2006) P, Pleasure D, Penninger JM, Tournier C & Itoh A
Protein kinase Cdelta-mediated proteasomal (2014) ZPK/DLK and MKK4 form the critical
degradation of MAP kinase phosphatase-1 contributes gateway to axotomy-induced motoneuron death in
to glutamate-induced neuronal cell death. J Cell Sci neonates. J Neurosci 34, 10729–10742.
119, 1329–1340. 53 Xia XG, Harding T, Weller M, Bieneman A, Uney JB
42 Kim AH, Yano H, Cho H, Meyer D, Monks B, & Schulz JB (2001) Gene transfer of the JNK
Margolis B, Birnbaum MJ & Chao MV (2002) Akt1 interacting protein-1 protects dopaminergic neurons in
the MPTP model of Parkinson’s disease. Proc Natl 66 Davila D, Connolly NM, Bonner H, Weisova P,
Acad Sci USA 98, 10433–10438. Dussmann H, Concannon CG, Huber HJ & Prehn JH
54 Levresse V, Butterfield L, Zentrich E & Heasley LE (2012) Two-step activation of FOXO3 by AMPK
(2000) Akt negatively regulates the cJun N-terminal generates a coherent feed-forward loop determining
kinase pathway in PC12 cells. J Neurosci Res 62, 799–808. excitotoxic cell fate. Cell Death Differ 19, 1677–1688.
55 Crowder RJ & Freeman RS (1998) 67 Zareen N, Biswas SC & Greene LA (2013) A feed-
Phosphatidylinositol 3-kinase and Akt protein kinase forward loop involving Trib3, Akt and FoxO mediates
are necessary and sufficient for the survival of nerve death of NGF-deprived neurons. Cell Death Differ 20,
growth factor-dependent sympathetic neurons. J 1719–1730.
Neurosci 18, 2933–2943. 68 Saleem S & Biswas SC (2017) Tribbles pseudokinase 3
56 Linseman DA, Phelps RA, Bouchard RJ, Le SS, induces both apoptosis and autophagy in amyloid-
Laessig TA, McClure ML & Heidenreich KA (2002) beta-induced neuronal death. J Biol Chem 292, 2571–
Insulin-like growth factor-I blocks Bcl-2 interacting 2585.
mediator of cell death (Bim) induction and intrinsic 69 Xu Z, Maroney AC, Dobrzanski P, Kukekov NV &
death signaling in cerebellar granule neurons. J Greene LA (2001) The MLK family mediates c-Jun N-
Neurosci 22, 9287–9297. terminal kinase activation in neuronal apoptosis. Mol
57 Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Cell Biol 21, 4713–4724.
Y & Greenberg ME (1997) Akt phosphorylation of 70 Pozniak CD, Sengupta Ghosh A, Gogineni A, Hanson
BAD couples survival signals to the cell-intrinsic death JE, Lee SH, Larson JL, Solanoy H, Bustos D, Li H,
machinery. Cell 91, 231–241. Ngu H et al. (2013) Dual leucine zipper kinase is
58 Yano S, Tokumitsu H & Soderling TR (1998) Calcium required for excitotoxicity-induced neuronal
promotes cell survival through CaM-K kinase degeneration. J Exp Med 210, 2553–2567.
activation of the protein-kinase-B pathway. Nature 71 Watkins TA, Wang B, Huntwork-Rodriguez S, Yang
396, 584–587. J, Jiang Z, Eastham-Anderson J, Modrusan Z,
59 Kamada H, Nito C, Endo H & Chan PH (2007) Bad Kaminker JS, Tessier-Lavigne M & Lewcock JW
as a converging signaling molecule between survival (2013) DLK initiates a transcriptional program that
PI3-K/Akt and death JNK in neurons after transient couples apoptotic and regenerative responses to axonal
focal cerebral ischemia in rats. J Cereb Blood Flow injury. Proc Natl Acad Sci USA 110, 4039–4044.
Metab 27, 521–533. 72 Le Pichon CE, Meilandt WJ, Dominguez S, Solanoy
60 Zheng WH, Kar S & Quirion R (2000) Insulin-like H, Lin H, Ngu H, Gogineni A, Sengupta Ghosh A,
growth factor-1-induced phosphorylation of the Jiang Z, Lee SH et al. (2017) Loss of dual leucine
forkhead family transcription factor FKHRL1 is zipper kinase signaling is protective in animal models
mediated by Akt kinase in PC12 cells. J Biol Chem of neurodegenerative disease. Sci Transl Med 9,
275, 39152–39158. eaag0394. https://doi.org/10.1126/scitranslmed.aag0394
61 Zheng WH, Kar S & Quirion R (2002) FKHRL1 73 Nakata K, Abrams B, Grill B, Goncharov A, Huang
and its homologs are new targets of nerve growth X, Chisholm AD & Jin Y (2005) Regulation of a
factor Trk receptor signaling. J Neurochem 80, 1049– DLK-1 and p38 MAP kinase pathway by the ubiquitin
1061. ligase RPM-1 is required for presynaptic development.
62 Gan L, Zheng W, Chabot JG, Unterman TG & Cell 120, 407–420.
Quirion R (2005) Nuclear/cytoplasmic shuttling of the 74 Xiong X, Wang X, Ewanek R, Bhat P, Diantonio A &
transcription factor FoxO1 is regulated by Collins CA (2010) Protein turnover of the Wallenda/
neurotrophic factors. J Neurochem 93, 1209–1219. DLK kinase regulates a retrograde response to axonal
63 Akhter R, Sanphui P & Biswas SC (2014) The injury. J Cell Biol 191, 211–223.
essential role of p53-up-regulated modulator of 75 Huntwork-Rodriguez S, Wang B, Watkins T, Ghosh
apoptosis (Puma) and its regulation by FoxO3a AS, Pozniak CD, Bustos D, Newton K, Kirkpatrick DS
transcription factor in beta-amyloid-induced neuron & Lewcock JW (2013) JNK-mediated phosphorylation
death. J Biol Chem 289, 10812–10822. of DLK suppresses its ubiquitination to promote
64 Sanphui P & Biswas SC (2013) FoxO3a is activated neuronal apoptosis. J Cell Biol 202, 747–763.
and executes neuron death via Bim in response to 76 Baker ST, Opperman KJ, Tulgren ED, Turgeon SM,
beta-amyloid. Cell Death Dis 4, e625. Bienvenut W & Grill B (2014) RPM-1 uses both
65 Li D, Luo L, Xu M, Wu J, Chen L, Li J, Liu Z, Lu ubiquitin ligase and phosphatase-based mechanisms to
G, Wang Y & Qiao L (2017) AMPK activates regulate DLK-1 during neuronal development. PLoS
FOXO3a and promotes neuronal apoptosis in the Genet 10, e1004297.
developing rat brain during the early phase after 77 Sarosiek KA, Fraser C, Muthalagu N, Bhola PD,
hypoxia-ischemia. Brain Res Bull 132, 1–9. Chang W, McBrayer SK, Cantlon A, Fisch S,
Golomb-Mello G, Ryan JA et al. (2017) death and is downregulated during the development of
Developmental regulation of mitochondrial apoptosis the nervous system. Development 124, 1239–1249.
by c-Myc governs age- and tissue-specific sensitivity to 89 Vogelbaum MA, Tong JX & Rich KM (1998)
cancer therapeutics. Cancer Cell 31, 142–156. Developmental regulation of apoptosis in dorsal root
78 Polster BM, Robertson CL, Bucci CJ, Suzuki M & ganglion neurons. J Neurosci 18, 8928–8935.
Fiskum G (2003) Postnatal brain development and 90 Easton RM, Deckwerth TL, Parsadanian AS &
neural cell differentiation modulate mitochondrial Bax Johnson EM Jr (1997) Analysis of the mechanism of
and BH3 peptide-induced cytochrome c release. Cell loss of trophic factor dependence associated with
Death Differ 10, 365–370. neuronal maturation: a phenotype indistinguishable
79 Zhu C, Wang X, Xu F, Bahr BA, Shibata M, from Bax deletion. J Neurosci 17, 9656–9666.
Uchiyama Y, Hagberg H & Blomgren K (2005) The 91 Krajewska M, Mai JK, Zapata JM, Ashwell KW,
influence of age on apoptotic and other mechanisms of Schendel SL, Reed JC & Krajewski S (2002)
cell death after cerebral hypoxia-ischemia. Cell Death Dynamics of expression of apoptosis-regulatory
Differ 12, 162–176. proteins Bid, Bcl-2, Bcl-X, Bax and Bak during
80 Krajewski S, Krajewska M & Reed JC (1996) development of murine nervous system. Cell Death
Immunohistochemical analysis of in vivo patterns of Differ 9, 145–157.
Bak expression, a proapoptotic member of the Bcl-2 92 Kole AJ, Swahari V, Hammond SM & Deshmukh M
protein family. Cancer Res 56, 2849–2855. (2011) miR-29b is activated during neuronal
81 Shimohama S, Fujimoto S, Sumida Y & Tanino H maturation and targets BH3-only genes to restrict
(1998) Differential expression of rat brain bcl-2 family apoptosis. Genes Dev 25, 125–130.
proteins in development and aging. Biochem Biophys 93 Wu F, Wang Z, Gu JH, Ge JB, Liang ZQ & Qin ZH
Res Commun 252, 92–96. (2013) p38(MAPK)/p53-Mediated Bax induction
82 Lindsten T, Ross AJ, King A, Zong WX, Rathmell contributes to neurons degeneration in rotenone-
JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, induced cellular and rat models of Parkinson’s disease.
Frauwirth K et al. (2000) The combined functions of Neurochem Int 63, 133–140.
proapoptotic Bcl-2 family members bak and bax are 94 Krajewski S, Mai JK, Krajewska M, Sikorska M,
essential for normal development of multiple tissues. Mossakowski MJ & Reed JC (1995) Upregulation of
Mol Cell 6, 1389–1399. bax protein levels in neurons following cerebral
83 Deckwerth TL, Elliott JL, Knudson CM, Johnson ischemia. J Neurosci 15, 6364–6376.
EM, Snider WD & Korsmeyer SJ (1996) BAX is 95 Mu X, He J, Anderson DW, Trojanowski JQ &
required for neuronal death after trophic factor Springer JE (1996) Altered expression of bcl-2 and bax
deprivation and during development. Neuron 17, 401– mRNA in amyotrophic lateral sclerosis spinal cord
411. motor neurons. Ann Neurol 40, 379–386.
84 Miller TM, Moulder KL, Knudson CM, Creedon DJ, 96 Isenmann S, Wahl C, Krajewski S, Reed JC & Bahr M
Deshmukh M, Korsmeyer SJ & Johnson EM (1997) (1997) Up-regulation of Bax protein in degenerating
Bax deletion further orders the cell death pathway in retinal ganglion cells precedes apoptotic cell death
cerebellar granule cells and suggests a caspase- after optic nerve lesion in the rat. Eur J Neurosci 9,
independent pathway to cell death. J Cell Biol 139, 1763–1772.
205–217. 97 Sun YF, Yu LY, Saarma M, Timmusk T & Arumae
85 Xiang H, Kinoshita Y, Knudson CM, Korsmeyer SJ, U (2001) Neuron-specific Bcl-2 homology 3 domain-
Schwartzkroin PA & Morrison RS (1998) Bax only splice variant of Bak is anti-apoptotic in neurons,
involvement in p53-mediated neuronal cell death. J but pro-apoptotic in non-neuronal cells. J Biol Chem
Neurosci 18, 1363–1373. 276, 16240–16247.
86 Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, 98 Uo T, Kinoshita Y & Morrison RS (2005) Neurons
Liberatore G, Offen D, Korsmeyer SJ & Przedborski S exclusively express N-Bak, a BH3 domain-only Bak
(2001) Bax ablation prevents dopaminergic isoform that promotes neuronal apoptosis. J Biol
neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6- Chem 280, 9065–9073.
tetrahydropyridine mouse model of Parkinson’s disease. 99 Fannjiang Y, Kim CH, Huganir RL, Zou S, Lindsten T,
Proc Natl Acad Sci USA 98, 2837–2842. Thompson CB, Mito T, Traystman RJ, Larsen T,
87 Kudo W, Lee HP, Smith MA, Zhu X, Matsuyama S Griffin DE et al. (2003) BAK alters neuronal excitability
& Lee HG (2012) Inhibition of Bax protects neuronal and can switch from anti- to pro-death function during
cells from oligomeric Abeta neurotoxicity. Cell Death postnatal development. Dev Cell 4, 575–585.
Dis 3, e309. 100 Pena-Blanco A & Garcia-Saez AJ (2018) Bax, Bak and
88 Vekrellis K, McCarthy MJ, Watson A, Whitfield J, beyond – mitochondrial performance in apoptosis.
Rubin LL & Ham J (1997) Bax promotes neuronal cell FEBS J 285, 416–431.
101 Uren RT, Iyer S & Kluck RM (2017) Pore formation 113 Murphy B, Dunleavy M, Shinoda S, Schindler C,
by dimeric Bak and Bax: an unusual pore? Philos Meller R, Bellver-Estelles C, Hatazaki S, Dicker P,
Trans R Soc Lond B Biol Sci 372, pii:20160218. Yamamoto A, Koegel I et al. (2007) Bcl-w protects
https://doi.org/10.1098/rstb.2016.0218 hippocampus during experimental status epilepticus.
102 Edlich F, Banerjee S, Suzuki M, Cleland Megan M, Am J Pathol 171, 1258–1268.
Arnoult D, Wang C, Neutzner A, Tjandra N & Youle 114 Courchesne SL, Karch C, Pazyra-Murphy MF &
Richard J (2011) Bcl-xL retrotranslocates Bax from Segal RA (2011) Sensory neuropathy attributable to
the mitochondria into the cytosol. Cell 145, 104–116. loss of Bcl-w. J Neurosci 31, 1624–1634.
103 Arbour N, Vanderluit JL, Le Grand JN, Jahani-Asl 115 Simon DJ, Pitts J, Hertz NT, Yang J, Yamagishi Y,
A, Ruzhynsky VA, Cheung EC, Kelly MA, Olsen O, Tesic Mark M, Molina H & Tessier-Lavigne
MacKenzie AE, Park DS, Opferman JT et al. (2008) M (2016) Axon degeneration gated by retrograde
Mcl-1 is a key regulator of apoptosis during CNS activation of somatic pro-apoptotic signaling. Cell 164,
development and after DNA damage. J Neurosci 28, 1031–1045.
6068–6078. 116 Madden SD, Donovan M & Cotter TG (2007) Key
104 Fogarty LC, Flemmer RT, Geizer BA, Licursi M, apoptosis regulating proteins are down-regulated
Karunanithy A, Opferman JT, Hirasawa K & during postnatal tissue development. Int J Dev Biol 51,
Vanderluit JL (2018) Mcl-1 and Bcl-xL are essential for 415–423.
survival of the developing nervous system. Cell Death 117 Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T
Differ. https://doi.org/10.1038/s41418-018-0225-1 & Tohyama M (1997) Molecular cloning of a novel
105 Crowther AJ, Gama V, Bevilacqua A, Chang SX, polypeptide, DP5, induced during programmed
Yuan H, Deshmukh M & Gershon TR (2013) Tonic neuronal death. J Biol Chem 272, 18842–18848.
activation of Bax primes neural progenitors for rapid 118 Kanazawa K, Imaizumi K, Mori T, Honma Y, Tojo
apoptosis through a mechanism preserved in M, Tanno Y, Yokoya S, Niwa S, Tohyama M, Takagi
medulloblastoma. J Neurosci 33, 18098–18108. T et al. (1998) Expression pattern of a novel death-
106 Malone CD, Hasan SM, Roome RB, Xiong J, promoting gene, DP5, in the developing murine
Furlong M, Opferman JT & Vanderluit JL (2012) nervous system. Brain Res Mol Brain Res 54, 316–320.
Mcl-1 regulates the survival of adult neural precursor 119 Putcha GV, Moulder KL, Golden JP, Bouillet P,
cells. Mol Cell Neurosci 49, 439–447. Adams JA, Strasser A & Johnson EM (2001)
107 Nakamura A, Swahari V, Plestant C, Smith I, McCoy Induction of BIM, a proapoptotic BH3-only BCL-2
E, Smith S, Moy SS, Anton ES & Deshmukh M family member, is critical for neuronal apoptosis.
(2016) Bcl-xL is essential for the survival and function Neuron 29, 615–628.
of differentiated neurons in the cortex that control 120 Coultas L, Terzano S, Thomas T, Voss A, Reid K,
complex behaviors. J Neurosci 36, 5448–5461. Stanley EG, Scott CL, Bouillet P, Bartlett P, Ham J
108 Merry DE, Veis DJ, Hickey WF & Korsmeyer SJ et al. (2007) Hrk/DP5 contributes to the apoptosis of
(1994) Bcl-2 protein expression is widespread in the select neuronal populations but is dispensable for
developing nervous-system and retained in the adult haematopoietic cell apoptosis. J Cell Sci 120, 2044–
Pns. Development 120, 301–311. 2052.
109 Michaelidis TM, Sendtner M, Cooper JD, Airaksinen 121 Wyttenbach A & Tolkovsky AM (2006) The BH3-only
MS, Holtmann B, Meyer M & Thoenen H (1996) protein Puma is both necessary and sufficient for
Inactivation of bcl-2 results in progressive neuronal apoptosis induced by DNA damage in
degeneration of motoneurons, sympathetic and sensory sympathetic neurons. J Neurochem 96, 1213–1226.
neurons during early postnatal development. Neuron 122 Akhter R, Saleem S, Saha A & Biswas SC (2018) The
17, 75–89. pro-apoptotic protein Bmf co-operates with Bim and
110 Hochman A, Sternin H, Gorodin S, Korsmeyer S, Ziv Puma in neuron death induced by beta-amyloid or
I, Melamed E & Offen D (1998) Enhanced oxidative NGF deprivation. Mol Cell Neurosci 88, 249–257.
stress and altered antioxidants in brains of Bcl-2- 123 Concannon CG, Tuffy LP, Weisova P, Bonner HP,
deficient mice. J Neurochem 71, 741–748. Davila D, Bonner C, Devocelle MC, Strasser A, Ward
111 Hamner S, Skoglosa Y & Lindholm D (1999) MW & Prehn JH (2010) AMP kinase-mediated
Differential expression of bcl-w and bcl-x messenger activation of the BH3-only protein Bim couples energy
RNA in the developing and adult rat nervous system. depletion to stress-induced apoptosis. J Cell Biol 189,
Neuroscience 91, 673–684. 83–94.
112 Middleton G, Wyatt S, Ninkina N & Davies AM 124 Fernandes KA, Harder JM, Kim J & Libby RT (2013)
(2001) Reciprocal developmental changes in the roles JUN regulates early transcriptional responses to
of Bcl-w and Bcl-x(L) in regulating sensory neuron axonal injury in retinal ganglion cells. Exp Eye Res
survival. Development 128, 447–457. 112, 106–117.
125 Harder JM & Libby RT (2013) Deficiency in Bim, Bid cells: inhibitory effects of several drugs. Neurochem Int
and Bbc3 (Puma) do not prevent axonal injury 25, 419–424.
induced death. Cell Death Differ 20, 182. 137 Imaizumi K, Morihara T, Mori Y, Katayama T,
126 Imaizumi K, Benito A, Kiryu-Seo S, Gonzalez V, Tsuda M, Furuyama T, Wanaka A, Takeda M &
Inohara N, Lieberman AP, Kiyama H & Nunez G Tohyama M (1999) The cell death-promoting gene
(2004) Critical role for DP5/Harakiri, a Bcl-2 DP5, which interacts with the BCL2 family, is induced
homology domain 3-only Bcl-2 family member, in during neuronal apoptosis following exposure to
axotomy-induced neuronal cell death. J Neurosci 24, amyloid beta protein. J Biol Chem 274, 7975–7981.
3721–3725. 138 Lobner D & Choi DW (1996) Preincubation with
127 Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan protein synthesis inhibitors protects cortical neurons
P, Drummond-Main C, Poulter MO, Ferguson SS, against oxygen-glucose deprivation-induced death.
Strasser A & Cregan SP (2007) Puma is a dominant Neuroscience 72, 335–341.
regulator of oxidative stress induced Bax activation 139 Du C, Hu R, Csernansky CA, Liu XZ, Hsu CY &
and neuronal apoptosis. J Neurosci 27, 12989–12999. Choi DW (1996) Additive neuroprotective effects of
128 Kieran D, Woods I, Villunger A, Strasser A & Prehn dextrorphan and cycloheximide in rats subjected to
JH (2007) Deletion of the BH3-only protein puma transient focal cerebral ischemia. Brain Res 718, 233–
protects motoneurons from ER stress-induced 236.
apoptosis and delays motoneuron loss in ALS mice. 140 Finiels F, Robert JJ, Samolyk ML, Privat A, Mallet J
Proc Natl Acad Sci USA 104, 20606–20611. & Revah F (1995) Induction of neuronal apoptosis by
129 Kuroki K, Virard I, Concannon CG, Engel T, Woods excitotoxins associated with long-lasting increase of
I, Taki W, Plesnila N, Henshall DC & Prehn JH 12-O-tetradecanoylphorbol 13-acetate-responsive
(2009) Effects of transient focal cerebral ischemia in element-binding activity. J Neurochem 65, 1027–1034.
mice deficient in puma. Neurosci Lett 451, 237–240. 141 Centeno C, Repici M, Chatton JY, Riederer BM,
130 Ren D, Tu HC, Kim H, Wang GX, Bean GR, Bonny C, Nicod P, Price M, Clarke PG, Papa S,
Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ & Franzoso G et al. (2007) Role of the JNK pathway in
Cheng EH (2010) BID, BIM, and PUMA are essential NMDA-mediated excitotoxicity of cortical neurons.
for activation of the BAX- and BAK-dependent cell Cell Death Differ 14, 240–253.
death program. Science 330, 1390–1393. 142 Whitfield J, Neame SJ, Paquet L, Bernard O & Ham J
131 Fricker M, Papadia S, Hardingham GE & Tolkovsky (2001) Dominant-negative c-Jun promotes neuronal
AM (2010) Implication of TAp73 in the p53- survival by reducing BIM expression and inhibiting
independent pathway of Puma induction and Puma- mitochondrial cytochrome c release. Neuron 29, 629–
dependent apoptosis in primary cortical neurons. J 643.
Neurochem 114, 772–783. 143 Biswas SC, Shi Y, Sproul A & Greene LA (2007) Pro-
132 Wong HK, Fricker M, Wyttenbach A, Villunger A, apoptotic Bim induction in response to nerve growth
Michalak EM, Strasser A & Tolkovsky AM (2005) factor deprivation requires simultaneous activation of
Mutually exclusive subsets of BH3-only proteins are three different death signaling pathways. J Biol Chem
activated by the p53 and c-Jun N-terminal kinase/c- 282, 29368–29374.
Jun signaling pathways during cortical neuron 144 Pirianov G, Brywe KG, Mallard C, Edwards AD,
apoptosis induced by arsenite. Mol Cell Biol 25, 8732– Flavell RA, Hagberg H & Mehmet H (2007) Deletion
8747. of the c-Jun N-terminal kinase 3 gene protects
133 Martin DP, Schmidt RE, DiStefano PS, Lowry OH, neonatal mice against cerebral hypoxic-ischaemic
Carter JG & Johnson EM Jr (1988) Inhibitors of injury. J Cereb Blood Flow Metab 27, 1022–1032.
protein synthesis and RNA synthesis prevent neuronal 145 Gao Y, Signore AP, Yin W, Cao G, Yin XM, Sun F,
death caused by nerve growth factor deprivation. J Luo Y, Graham SH & Chen J (2005) Neuroprotection
Cell Biol 106, 829–844. against focal ischemic brain injury by inhibition of c-
134 D’Mello SR, Galli C, Ciotti T & Calissano P (1993) Jun N-terminal kinase and attenuation of the
Induction of apoptosis in cerebellar granule neurons mitochondrial apoptosis-signaling pathway. J Cereb
by low potassium: inhibition of death by insulin-like Blood Flow Metab 25, 694–712.
growth factor I and cAMP. Proc Natl Acad Sci USA 146 Aleyasin H, Cregan SP, Iyirhiaro G, O’Hare MJ,
90, 10989–10993. Callaghan SM, Slack RS & Park DS (2004) Nuclear
135 Garcia-Valenzuela E, Gorczyca W, Darzynkiewicz Z factor-(kappa)B modulates the p53 response in neurons
& Sharma SC (1994) Apoptosis in adult retinal exposed to DNA damage. J Neurosci 24, 2963–2973.
ganglion cells after axotomy. J Neurobiol 25, 431–438. 147 Cregan SP, Arbour NA, MacLaurin JG, Callaghan
136 Itano Y, Kitamura Y & Nomura Y (1994) 1-Methyl-4- SM, Fortin A, Cheung ECC, Guberman DS, Park DS
phenylpyridinium (MPP+)-induced cell death in PC12 & Slack RS (2004) p53 activation domain 1 is essential
for PUMA upregulation and p53-mediated neuronal levels in 3-nitropropionic acid-treated cortical neurons.
cell death. J Neurosci 24, 10003–10012. Neurobiol Dis 35, 448–456.
148 Engel T, Murphy BM, Hatazaki S, Jimenez-Mateos 161 Ordonez AN, Jessick VJ, Clayton CE, Ashley MD,
EM, Concannon CG, Woods I, Prehn JH & Henshall Thompson SJ, Simon RP & Meller R (2010) Rapid
DC (2010) Reduced hippocampal damage and ischemic tolerance induced by adenosine
epileptic seizures after status epilepticus in mice preconditioning results in Bcl-2 interacting mediator of
lacking proapoptotic Puma. FASEB J 24, 853–861. cell death (Bim) degradation by the proteasome. Int J
149 Qi X, Davis B, Chiang YH, Filichia E, Barnett A, Physiol Pathophysiol Pharmacol 2, 36–44.
Greig NH, Hoffer B & Luo Y (2016) Dopaminergic 162 Lelievre EC, Plestant C, Boscher C, Wolff E, Mege
neuron-specific deletion of p53 gene is neuroprotective RM & Birbes H (2012) N-cadherin mediates neuronal
in an experimental Parkinson’s disease model. J cell survival through Bim down-regulation. PLoS One
Neurochem 138, 746–757. 7, e33206.
150 Ghosh AP, Klocke BJ, Ballestas ME & Roth KA 163 Thompson S, Pearson AN, Ashley MD, Jessick V,
(2012) CHOP potentially co-operates with FOXO3a in Murphy BM, Gafken P, Henshall DC, Morris KT,
neuronal cells to regulate PUMA and BIM expression Simon RP & Meller R (2011) Identification of a
in response to ER stress. PLoS One 7, e39586. novel Bcl-2-interacting mediator of cell death (Bim)
151 Galehdar Z, Swan P, Fuerth B, Callaghan SM, Park E3 ligase, tripartite motif-containing protein 2
DS & Cregan SP (2010) Neuronal apoptosis induced (TRIM2), and its role in rapid ischemic tolerance-
by endoplasmic reticulum stress is regulated by ATF4- induced neuroprotection. J Biol Chem 286, 19331–
CHOP-mediated induction of the Bcl-2 homology 3- 19339.
only member PUMA. J Neurosci 30, 16938–16948. 164 Bonni A, Brunet A, West AE, Datta SR, Takasu MA
152 Yuan Z, Lehtinen MK, Merlo P, Villen J, Gygi S & & Greenberg ME (1999) Cell survival promoted by the
Bonni A (2009) Regulation of neuronal cell death by Ras-MAPK signaling pathway by transcription-
MST1-FOXO1 signaling. J Biol Chem 284, 11285–11292. dependent and -independent mechanisms. Science 286,
153 Shi C, Viccaro K, Lee HG & Shah K (2016) Cdk5- 1358–1362.
Foxo3 axis: initially neuroprotective, eventually 165 Roberts ML, Virdee K, Sampson CP, Gordon I,
neurodegenerative in Alzheimer’s disease models. J Parone P & Tolkovsky AM (2000) The combination
Cell Sci 129, 1815–1830. of bcl-2 expression and NGF-deprivation facilitates
154 Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly the selective destruction of BAD protein in living
PN, Huntington ND, Hughes PD, Michalak EM, sympathetic neurons. Mol Cell Neurosci 16, 97–110.
McKimm-Breschkin J, Motoyama N et al. (2007) ER 166 Huang HY, Lin SZ, Kuo JS, Chen WF & Wang MJ
stress triggers apoptosis by activating BH3-only (2007) G-CSF protects dopaminergic neurons from 6-
protein Bim. Cell 129, 1337–1349. OHDA-induced toxicity via the ERK pathway.
155 Matus S, Lopez E, Valenzuela V, Nassif M & Hetz C Neurobiol Aging 28, 1258–1269.
(2013) Functional contribution of the transcription 167 Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA,
factor ATF4 to the pathogenesis of amyotrophic Mannella CA & Korsmeyer SJ (2002) A distinct
lateral sclerosis. PLoS One 8, e66672. pathway remodels mitochondrial cristae and mobilizes
156 Biswas SC, Liu DX & Greene LA (2005) Bim is a cytochrome c during apoptosis. Dev Cell 2, 55–67.
direct target of a neuronal E2F-dependent apoptotic 168 Frezza C, Cipolat S, Martins de Brito O, Micaroni M,
pathway. J Neurosci 25, 8349–8358. Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS,
157 Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM Danial NN, De Strooper B et al. (2006) OPA1
& Greene LA (2007) Bim is elevated in Alzheimer’s controls apoptotic cristae remodeling independently
disease neurons and is required for beta-amyloid- from mitochondrial fusion. Cell 126, 177–189.
induced neuronal apoptosis. J Neurosci 27, 893–900. 169 Song Z, Chen H, Fiket M, Alexander C & Chan DC
158 Finegan KG, Wang X, Lee EJ, Robinson AC & (2007) OPA1 processing controls mitochondrial fusion
Tournier C (2009) Regulation of neuronal survival by and is regulated by mRNA splicing, membrane
the extracellular signal-regulated protein kinase 5. Cell potential, and Yme1L. J Cell Biol 178, 749–755.
Death Differ 16, 674–683. 170 Yamaguchi R, Lartigue L, Perkins G, Scott RT, Dixit
159 Biswas SC & Greene LA (2002) Nerve growth factor A, Kushnareva Y, Kuwana T, Ellisman MH &
(NGF) down-regulates the Bcl-2 homology 3 (BH3) Newmeyer DD (2008) Opa1-mediated cristae opening
domain-only protein Bim and suppresses its is Bax/Bak and BH3 dependent, required for
proapoptotic activity by phosphorylation. J Biol Chem apoptosis, and independent of Bak oligomerization.
277, 49511–49516. Mol Cell 31, 557–569.
160 Almeida S, Laco M, Cunha-Oliveira T, Oliveira CR & 171 Jiang X, Jiang H, Shen Z & Wang X (2014)
Rego AC (2009) BDNF regulates BIM expression Activation of mitochondrial protease OMA1 by Bax
and Bak promotes cytochrome c release during Ikonomidou C et al. (2010) Suppression of the
apoptosis. Proc Natl Acad Sci USA 111, 14782–14787. intrinsic apoptosis pathway by synaptic activity. J
172 Jiang X, Li L, Ying Z, Pan C, Huang S, Li L, Dai M, Neurosci 30, 2623–2635.
Yan B, Li M, Jiang H et al. (2016) A small molecule 184 Chang LK, Schmidt RE & Johnson EM Jr (2003)
that protects the integrity of the electron transfer Alternating metabolic pathways in NGF-deprived
chain blocks the mitochondrial apoptotic pathway. sympathetic neurons affect caspase-independent death.
Mol Cell 63, 229–239. J Cell Biol 162, 245–256.
173 Bertholet AM, Millet AM, Guillermin O, Daloyau M, 185 Krohn AJ, Wahlbrink T & Prehn JH (1999)
Davezac N, Miquel MC & Belenguer P (2013) OPA1 Mitochondrial depolarization is not required for
loss of function affects in vitro neuronal maturation. neuronal apoptosis. J Neurosci 19, 7394–7404.
Brain 136, 1518–1533. 186 Wigdal SS, Kirkland RA, Franklin JL & Haak-
174 Jahani-Asl A, Pilon-Larose K, Xu W, MacLaurin JG, Frendscho M (2002) Cytochrome c release precedes
Park DS, McBride HM & Slack RS (2011) The mitochondrial membrane potential loss in cerebellar
mitochondrial inner membrane GTPase, optic atrophy granule neuron apoptosis: lack of mitochondrial
1 (Opa1), restores mitochondrial morphology and swelling. J Neurochem 82, 1029–1038.
promotes neuronal survival following excitotoxicity. J 187 Chang LK & Johnson EM Jr (2002) Cyclosporin A
Biol Chem 286, 4772–4782. inhibits caspase-independent death of NGF-deprived
175 Korwitz A, Merkwirth C, Richter-Dennerlein R, sympathetic neurons: a potential role for
Troder SE, Sprenger HG, Quiros PM, Lopez-Otin C, mitochondrial permeability transition. J Cell Biol 157,
Rugarli EI & Langer T (2016) Loss of OMA1 delays 771–781.
neurodegeneration by preventing stress-induced OPA1 188 Brown GC & Borutaite V (2008) Regulation of
processing in mitochondria. J Cell Biol 212, 157–166. apoptosis by the redox state of cytochrome c. Biochim
176 Chang LK, Putcha GV, Deshmukh M & Johnson EM Biophys Acta 1777, 877–881.
(2002) Mitochondrial involvement in the point of no 189 Hancock JT, Desikan R & Neill SJ (2001) Does the
return in neuronal apoptosis. Biochimie 84, 223– redox status of cytochrome C act as a fail-safe
231. mechanism in the regulation of programmed cell
177 Galluzzi L, Vitale I, Aaronson SA, Abrams JM, death? Free Radic Biol Med 31, 697–703.
Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio 190 Kirkland RA & Franklin JL (2001) Evidence for
I, Andrews DW et al. (2018) Molecular mechanisms of redox regulation of cytochrome C release during
cell death: recommendations of the Nomenclature programmed neuronal death: antioxidant effects of
Committee on Cell Death 2018. Cell Death Differ 25, protein synthesis and caspase inhibition. J Neurosci 21,
486–541. 1949–1963.
178 Deshmukh M & Johnson EM Jr (1998) Evidence of a 191 Kirkland RA, Windelborn JA, Kasprzak JM &
novel event during neuronal death: development of Franklin JL (2002) A Bax-induced pro-oxidant state is
competence-to-die in response to cytoplasmic critical for cytochrome c release during programmed
cytochrome c. Neuron 21, 695–705. neuronal death. J Neurosci 22, 6480–6490.
179 Martinou I, Desagher S, Eskes R, Antonsson B, 192 Kirkland RA & Franklin JL (2003) Bax, reactive
Andre E, Fakan S & Martinou JC (1999) The release oxygen, and cytochrome c release in neuronal
of cytochrome c from mitochondria during apoptosis apoptosis. Antioxid Redox Signal 5, 589–596.
of NGF-deprived sympathetic neurons is a reversible 193 Greenlund LJ, Deckwerth TL & Johnson EM Jr
event. J Cell Biol 144, 883–889. (1995) Superoxide dismutase delays neuronal
180 Deshmukh M, Kuida K & Johnson EM Jr (2000) apoptosis: a role for reactive oxygen species in
Caspase inhibition extends the commitment to programmed neuronal death. Neuron 14, 303–315.
neuronal death beyond cytochrome c release to the 194 Kirkland RA, Saavedra GM & Franklin JL (2007)
point of mitochondrial depolarization. J Cell Biol 150, Rapid activation of antioxidant defenses by nerve
131–143. growth factor suppresses reactive oxygen species during
181 Vaughn AE & Deshmukh M (2008) Glucose neuronal apoptosis: evidence for a role in cytochrome c
metabolism inhibits apoptosis in neurons and cancer redistribution. J Neurosci 27, 11315–11326.
cells by redox inactivation of cytochrome c. Nat Cell 195 Gama V, Swahari V, Schafer J, Kole AJ, Evans A,
Biol 10, 1477–1483. Huang Y, Cliffe A, Golitz B, Sciaky N, Pei XH et al.
182 Neame SJ, Rubin LL & Philpott KL (1998) Blocking (2014) The E3 ligase PARC mediates the degradation
cytochrome c activity within intact neurons inhibits of cytosolic cytochrome c to promote survival in
apoptosis. J Cell Biol 142, 1583–1593. neurons and cancer cells. Sci Signal 7, ra67.
183 Leveille F, Papadia S, Fricker M, Bell KF, Soriano 196 Yakovlev AG, Ota K, Wang G, Movsesyan V, Bao
FX, Martel MA, Puddifoot C, Habel M, Wyllie DJ, WL, Yoshihara K & Faden AI (2001) Differential
expression of apoptotic protease-activating factor-1 209 Kawamoto Y, Ito H, Ayaki T & Takahashi R (2014)
and caspase-3 genes and susceptibility to apoptosis Immunohistochemical localization of apoptosome-
during brain development and after traumatic brain related proteins in Lewy bodies in Parkinson’s disease
injury. J Neurosci 21, 7439–7446. and dementia with Lewy bodies. Brain Res 1571, 39–
197 Wright KM, Linhoff MW, Potts PR & Deshmukh M 48.
(2004) Decreased apoptosome activity with neuronal 210 Giovanni A, Keramaris E, Morris EJ, Hou ST,
differentiation sets the threshold for strict IAP O’Hare M, Dyson N, Robertson GS, Slack RS &
regulation of apoptosis. J Cell Biol 167, 303–313. Park DS (2000) E2F1 mediates death of B-amyloid-
198 Riedl SJ & Salvesen GS (2007) The apoptosome: treated cortical neurons in a manner independent of
signalling platform of cell death. Nat Rev Mol Cell p53 and dependent on Bax and caspase 3. J Biol Chem
Biol 8, 405–413. 275, 11553–11560.
199 Bao Q, Riedl SJ & Shi Y (2005) Structure of Apaf-1 211 Herrup K, Neve R, Ackerman SL & Copani A (2004)
in the auto-inhibited form: a critical role for ADP. Divide and die: cell cycle events as triggers of nerve
Cell Cycle 4, 1001–1003. cell death. J Neurosci 24, 9232–9239.
200 Fortin A, Cregan SP, MacLaurin JG, Kushwaha N, 212 Hyman BT & Yuan J (2012) Apoptotic and non-
Hickman ES, Thompson CS, Hakim A, Albert PR, apoptotic roles of caspases in neuronal physiology and
Cecconi F, Helin K et al. (2001) APAF1 is a key pathophysiology. Nat Rev Neurosci 13, 395–406.
transcriptional target for p53 in the regulation of 213 Hu BR, Liu CL, Ouyang Y, Blomgren K & Siesjo BK
neuronal cell death. J Cell Biol 155, 207–216. (2000) Involvement of caspase-3 in cell death after
201 Wright KM, Smith MI, Farrag L & Deshmukh M hypoxia-ischemia declines during brain maturation. J
(2007) Chromatin modification of Apaf-1 restricts the Cereb Blood Flow Metab 20, 1294–1300.
apoptotic pathway in mature neurons. J Cell Biol 179, 214 Vanderluit JL, McPhail LT, Fernandes KJ, McBride
825–832. CB, Huguenot C, Roy S, Robertson GS, Nicholson
202 Moroni MC, Hickman ES, Lazzerini Denchi E, DW & Tetzlaff W (2000) Caspase-3 is activated
Caprara G, Colli E, Cecconi F, Muller H & Helin K following axotomy of neonatal facial motoneurons
(2001) Apaf-1 is a transcriptional target for E2F and and caspase-3 gene deletion delays axotomy-induced
p53. Nat Cell Biol 3, 552–558. cell death in rodents. Eur J Neurosci 12, 3469–3480.
203 Furukawa Y, Nishimura N, Furukawa Y, Satoh M, 215 Zhang X, Szabo E, Michalak M & Opas M (2007)
Endo H, Iwase S, Yamada H, Matsuda M, Kano Y & Endoplasmic reticulum stress during the embryonic
Nakamura M (2002) Apaf-1 is a mediator of E2F-1- development of the central nervous system in the
induced apoptosis. J Biol Chem 277, 39760–39768. mouse. Int J Dev Neurosci 25, 455–463.
204 Ota K, Yakovlev AG, Itaya A, Kameoka M, Tanaka 216 Ng PW, Porter AG & Janicke RU (1999) Molecular
Y & Yoshihara K (2002) Alteration of apoptotic cloning and characterization of two novel pro-
protease-activating factor-1 (APAF-1)-dependent apoptotic isoforms of caspase-10. J Biol Chem 274,
apoptotic pathway during development of rat brain 10301–10308.
and liver. J Biochem 131, 131–135. 217 Kumar S, Tomooka Y & Noda M (1992)
205 Donovan M & Cotter TG (2002) Caspase-independent Identification of a set of genes with developmentally
photoreceptor apoptosis in vivo and differential down-regulated expression in the mouse brain.
expression of apoptotic protease activating factor-1 Biochem Biophys Res Commun 185, 1155–1161.
and caspase-3 during retinal development. Cell Death 218 de Bilbao F, Guarin E, Nef P, Vallet P,
Differ 9, 1220–1231. Giannakopoulos P & Dubois-Dauphin M (1999)
206 Vaughn AE & Deshmukh M (2007) Essential Postnatal distribution of cpp32/caspase 3 mRNA in
postmitochondrial function of p53 uncovered in DNA the mouse central nervous system: an in situ
damage-induced apoptosis in neurons. Cell Death hybridization study. J Comp Neurol 409, 339–357.
Differ 14, 973–981. 219 Putcha GV, Deshmukh M & Johnson EM Jr (2000)
207 Chen Q, Xu J, Li L, Li H, Mao S, Zhang F, Zen K, Inhibition of apoptotic signaling cascades causes loss
Zhang CY & Zhang Q (2014) MicroRNA-23a/b and of trophic factor dependence during neuronal
microRNA-27a/b suppress Apaf-1 protein and maturation. J Cell Biol 149, 1011–1018.
alleviate hypoxia-induced neuronal apoptosis. Cell 220 McKernan DP, Caplis C, Donovan M, O’Brien C J &
Death Dis 5, e1132. Cotter TG (2006) Age-dependent susceptibility of the
208 Cozzolino M, Ferraro E, Ferri A, Rigamonti D, retinal ganglion cell layer to cell death. Invest
Quondamatteo F, Ding H, Xu ZS, Ferrari F, Angelini Ophthalmol Vis Sci 47, 807–814.
DF, Rotilio G et al. (2004) Apoptosome inactivation 221 Armstrong RC, Aja TJ, Hoang KD, Gaur S, Bai X,
rescues proneural and neural cells from Alnemri ES, Litwack G, Karanewsky DS, Fritz LC &
neurodegeneration. Cell Death Differ 11, 1179–1191. Tomaselli KJ (1997) Activation of the CED3/ICE-
related protease CPP32 in cerebellar granule neurons 233 Ni B, Wu X, Du Y, Su Y, Hamilton-Byrd E, Rockey

undergoing apoptosis but not necrosis. J Neurosci 17, PK, Rosteck P Jr, Poirier GG & Paul SM (1997)
553–562. Cloning and expression of a rat brain interleukin-
222 Moran J, Itoh T, Reddy UR, Chen M, Alnemri ES & 1beta-converting enzyme (ICE)-related protease (IRP)
Pleasure D (1999) Caspase-3 expression by cerebellar and its possible role in apoptosis of cultured cerebellar
granule neurons is regulated by calcium and cyclic granule neurons. J Neurosci 17, 1561–1569.
AMP. J Neurochem 73, 568–577. 234 Ni B, Wu X, Su Y, Stephenson D, Smalstig EB,
223 Du Y, Bales KR, Dodel RC, Hamilton-Byrd E, Horn Clemens J & Paul SM (1998) Transient global
JW, Czilli DL, Simmons LK, Ni B & Paul SM (1997) forebrain ischemia induces a prolonged expression of
Activation of a caspase 3-related cysteine protease is the caspase-3 mRNA in rat hippocampal CA1
required for glutamate-mediated apoptosis of cultured pyramidal neurons. J Cereb Blood Flow Metab 18,
cerebellar granule neurons. Proc Natl Acad Sci USA 248–256.
94, 11657–11662. 235 Sabbagh L, Bourbonniere M, Denis F & Sekaly RP
224 Tenneti L, D’Emilia DM, Troy CM & Lipton SA (2006) Cloning and functional characterization of the
(1998) Role of caspases in N-methyl-D-aspartate- murine caspase-3 gene promoter. DNA Cell Biol 25,
induced apoptosis in cerebrocortical neurons. J 104–115.
Neurochem 71, 946–959. 236 Ehrnhoefer DE, Skotte NH, Ladha S, Nguyen YT,
225 Savinainen A, Garcia EP, Dorow D, Marshall J & Liu Qiu X, Deng Y, Huynh KT, Engemann S, Nielsen
YF (2001) Kainate receptor activation induces mixed SM, Becanovic K et al. (2014) p53 increases caspase-6
lineage kinase-mediated cellular signaling cascades via expression and activation in muscle tissue expressing
post-synaptic density protein 95. J Biol Chem 276, mutant huntingtin. Hum Mol Genet 23, 717–729.
11382–11386. 237 Song B, Xie B, Wang C & Li M (2011) Caspase-3 is a
226 Hara H, Friedlander RM, Gagliardini V, Ayata C, target gene of c-Jun:ATF2 heterodimers during
Fink K, Huang Z, Shimizu-Sasamata M, Yuan J & apoptosis induced by activity deprivation in cerebellar
Moskowitz MA (1997) Inhibition of interleukin 1beta granule neurons. Neurosci Lett 505, 76–81.
converting enzyme family proteases reduces ischemic 238 Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van
and excitotoxic neuronal damage. Proc Natl Acad Sci Dongen JL, Gilfillan MC, Shiels H, Hardwick JM &
USA 94, 2007–2012. Thompson CB (1996) A conserved family of cellular
227 Katai N & Yoshimura N (1999) Apoptotic retinal genes related to the baculovirus iap gene and encoding
neuronal death by ischemia-reperfusion is executed by apoptosis inhibitors. EMBO J 15, 2685–2694.
two distinct caspase family proteases. Invest 239 Crook NE, Clem RJ & Miller LK (1993) An
Ophthalmol Vis Sci 40, 2697–2705. apoptosis-inhibiting baculovirus gene with a zinc
228 Kermer P, Klocker N, Labes M & Bahr M (1998) finger-like motif. J Virol 67, 2168–2174.
Inhibition of CPP32-like proteases rescues axotomized 240 Srinivasula SM & Ashwell JD (2008) IAPs: what’s in a
retinal ganglion cells from secondary cell death name? Mol Cell 30, 123–135.
in vivo. J Neurosci 18, 4656–4662. 241 Lalaoui N & Vaux DL (2018) Recent advances in
229 Kermer P, Ankerhold R, Klocker N, Krajewski S, understanding inhibitor of apoptosis proteins. F1000Res
Reed JC & Bahr M (2000) Caspase-9: involvement in 7, pii:F1000. https://doi.org/10.12688/f1000research.
secondary death of axotomized rat retinal ganglion 16439.1
cells in vivo. Brain Res Mol Brain Res 85, 144–150. 242 Silke J & Meier P (2013) Inhibitor of apoptosis (IAP)
230 Colak A, Karaoglan A, Barut S, Kokturk S, Akyildiz proteins-modulators of cell death and inflammation.
AI & Tasyurekli M (2005) Neuroprotection and Cold Spring Harb Perspect Biol 5, a008730.
functional recovery after application of the caspase-9 243 Eckelman BP, Salvesen GS & Scott FL (2006) Human
inhibitor z-LEHD-fmk in a rat model of traumatic inhibitor of apoptosis proteins: why XIAP is the black
spinal cord injury. J Neurosurg Spine 2, 327–334. sheep of the family. EMBO Rep 7, 988–994.
231 Dodel RC, Du Y, Bales KR, Ling ZD, Carvey PM & 244 Eckelman BP & Salvesen GS (2006) The human anti-
Paul SM (1998) Peptide inhibitors of caspase-3-like apoptotic proteins cIAP1 and cIAP2 bind but do not
proteases attenuate 1-methyl-4-phenylpyridinum- inhibit caspases. J Biol Chem 281, 3254–3260.
induced toxicity of cultured fetal rat mesencephalic 245 Roy N, Deveraux QL, Takahashi R, Salvesen GS &
dopamine neurons. Neuroscience 86, 701–707. Reed JC (1997) The c-IAP-1 and c-IAP-2 proteins are
232 Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, direct inhibitors of specific caspases. EMBO J 16,
Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, 6914–6925.
Przedborski S et al. (2000) Functional role of caspase- 246 Simons M, Beinroth S, Gleichmann M, Liston P,
1 and caspase-3 in an ALS transgenic mouse model. Korneluk RG, MacKenzie AE, Bahr M, Klockgether
Science 288, 335–339. T, Robertson GS, Weller M et al. (1999) Adenovirus-
mediated gene transfer of inhibitors of apoptosis 257 McKinnon SJ, Lehman DM, Tahzib NG, Ransom
protein delays apoptosis in cerebellar granule neurons. NL, Reitsamer HA, Liston P, LaCasse E, Li Q,
J Neurochem 72, 292–301. Korneluk RG & Hauswirth WW (2002) Baculoviral
247 Yu LY, Korhonen L, Martinez R, Jokitalo E, Chen IAP repeat-containing-4 protects optic nerve axons in
Y, Arumae U & Lindholm D (2003) Regulation of a rat glaucoma model. Mol Ther 5, 780–787.
sympathetic neuron and neuroblastoma cell death by 258 Leonard KC, Petrin D, Coupland SG, Baker AN,
XIAP and its association with proteasomes in neural Leonard BC, LaCasse EC, Hauswirth WW, Korneluk
cells. Mol Cell Neurosci 22, 308–318. RG & Tsilfidis C (2007) XIAP protection of
248 Wiese S, Digby MR, Gunnersen JM, Gotz R, Pei G, photoreceptors in animal models of retinitis
Holtmann B, Lowenthal J & Sendtner M (1999) The pigmentosa. PLoS One 2, e314.
anti-apoptotic protein ITA is essential for NGF- 259 Troy CM, Rabacchi SA, Hohl JB, Angelastro JM,
mediated survival of embryonic chick neurons. Nat Greene LA & Shelanski ML (2001) Death in the
Neurosci 2, 978–983. balance: alternative participation of the caspase-2 and
249 Kugler S, Straten G, Kreppel F, Isenmann S, Liston P -9 pathways in neuronal death induced by nerve
& Bahr M (2000) The X-linked inhibitor of apoptosis growth factor deprivation. J Neurosci 21, 5007–5016.
(XIAP) prevents cell death in axotomized CNS 260 Perrelet D, Ferri A, Liston P, Muzzin P, Korneluk
neurons in vivo. Cell Death Differ 7, 815–824. RG & Kato AC (2002) IAPs are essential for GDNF-
250 Xu D, Bureau Y, McIntyre DC, Nicholson DW, Liston mediated neuroprotective effects in injured motor
P, Zhu Y, Fong WG, Crocker SJ, Korneluk RG & neurons in vivo. Nat Cell Biol 4, 175–179.
Robertson GS (1999) Attenuation of ischemia-induced 261 Blancas S, Fado R, Rodriguez-Alvarez J & Moran J
cellular and behavioral deficits by X chromosome- (2014) Endogenous XIAP, but not other members of
linked inhibitor of apoptosis protein overexpression in the inhibitory apoptosis protein family modulates
the rat hippocampus. J Neurosci 19, 5026–5033. cerebellar granule neurons survival. Int J Dev Neurosci
251 Trapp T, Korhonen L, Besselmann M, Martinez R, 37, 26–35.
Mercer EA & Lindholm D (2003) Transgenic mice 262 Potts PR, Singh S, Knezek M, Thompson CB &
overexpressing XIAP in neurons show better outcome Deshmukh M (2003) Critical function of endogenous
after transient cerebral ischemia. Mol Cell Neurosci 23, XIAP in regulating caspase activation during
302–313. sympathetic neuronal apoptosis. J Cell Biol 163, 789–
252 Wang X, Zhu C, Wang X, Hagberg H, Korhonen L, 799.
Sandberg M, Lindholm D & Blomgren K (2004) X- 263 West T, Stump M, Lodygensky G, Neil JJ, Deshmukh
linked inhibitor of apoptosis (XIAP) protein protects M & Holtzman DM (2009) Lack of X-linked inhibitor
against caspase activation and tissue loss after of apoptosis protein leads to increased apoptosis and
neonatal hypoxia-ischemia. Neurobiol Dis 16, 179–189. tissue loss following neonatal brain injury. ASN Neuro
253 Eberhardt O, Coelln RV, Kugler S, Lindenau J, 1, pii:e00004. https://doi.org/0.1042/AN20090005
Rathke-Hartlieb S, Gerhardt E, Haid S, Isenmann S, 264 Harlin H, Reffey SB, Duckett CS, Lindsten T &
Gravel C, Srinivasan A et al. (2000) Protection by Thompson CB (2001) Characterization of XIAP-
synergistic effects of adenovirus-mediated X- deficient mice. Mol Cell Biol 21, 3604–3608.
chromosome-linked inhibitor of apoptosis and glial 265 Korhonen L, Belluardo N & Lindholm D (2001)
cell line-derived neurotrophic factor gene transfer in Regulation of X-chromosome-linked inhibitor of
the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model apoptosis protein in kainic acid-induced neuronal
of Parkinson’s disease. J Neurosci 20, 9126–9134. death in the rat hippocampus. Mol Cell Neurosci 17,
254 Crocker SJ, Liston P, Anisman H, Lee CJ, Smith PD, 364–372.
Earl N, Thompson CS, Park DS, Korneluk RG & 266 Lotocki G & Keane RW (2002) Inhibitors of
Robertson GS (2003) Attenuation of MPTP-induced apoptosis proteins in injury and disease. IUBMB Life
neurotoxicity and behavioural impairment in NSE- 54, 231–240.
XIAP transgenic mice. Neurobiol Dis 12, 150–161. 267 Tsang AH, Lee YI, Ko HS, Savitt JM, Pletnikova O,
255 Inoue H, Tsukita K, Iwasato T, Suzuki Y, Tomioka Troncoso JC, Dawson VL, Dawson TM & Chung KK
M, Tateno M, Nagao M, Kawata A, Saido TC, Miura (2009) S-nitrosylation of XIAP compromises neuronal
M et al. (2003) The crucial role of caspase-9 in the survival in Parkinson’s disease. Proc Natl Acad Sci
disease progression of a transgenic ALS mouse model. USA 106, 4900–4905.
EMBO J 22, 6665–6674. 268 Smith MI, Huang YY & Deshmukh M (2009) Skeletal
256 Wootz H, Hansson I, Korhonen L & Lindholm D muscle differentiation evokes endogenous XIAP to
(2006) XIAP decreases caspase-12 cleavage and restrict the apoptotic pathway. PLoS One 4, e5097.
calpain activity in spinal cord of ALS transgenic mice. 269 Lee H, Shin EA, Lee JH, Ahn D, Kim CG, Kim JH
Exp Cell Res 312, 1890–1898. & Kim SH (2018) Caspase inhibitors: a review of
recently patented compounds (2013–2015). Expert 274 Lankiewicz S, Marc Luetjens C, Truc Bui N, Krohn
Opin Ther Pat 28, 47–59. AJ, Poppe M, Cole GM, Saido TC & Prehn JH (2000)
270 Morris G, Walker AJ, Berk M, Maes M & Puri BK Activation of calpain I converts excitotoxic neuron
(2018) Cell death pathways: a novel therapeutic death into a caspase-independent cell death. J Biol
approach for neuroscientists. Mol Neurobiol 55, 5767– Chem 275, 17064–17071.
5786. 275 Volbracht C, Chua BT, Ng CP, Bahr BA, Hong W &
271 Yuan J, Amin P & Ofengeim D (2019) Necroptosis Li P (2005) The critical role of calpain versus caspase
and RIPK1-mediated neuroinflammation in CNS activation in excitotoxic injury induced by nitric oxide.
diseases. Nat Rev Neurosci 20, 19–33. J Neurochem 93, 1280–1292.
272 McGinnis KM, Gnegy ME, Park YH, Mukerjee N & 276 Geden MJ, Romero SE & Deshmukh M (2018)
Wang KK (1999) Procaspase-3 and poly(ADP)ribose Apoptosis versus axon pruning: molecular intersection
polymerase (PARP) are calpain substrates. Biochem of two distinct pathways for axon degeneration.
Biophys Res Commun 263, 94–99. Neurosci Res 139, 3–8.
273 Chua BT, Guo K & Li P (2000) Direct cleavage by 277 Hollville E & Deshmukh M (2018) Physiological
the calcium-activated protease calpain can lead to functions of non-apoptotic caspase activity in the
inactivation of caspases. J Biol Chem 275, 5131–5135. nervous system. Semin Cell Dev Biol 82, 127–136.

The FEBS Journal - 2019 - Hollville - Apoptotic Cell Death Regulation in Neurons

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The FEBS Journal - 2019 - Hollville - Apoptotic Cell Death Regulation in Neurons

Uploaded by

Copyright:

Available Formats

STATE-OF-THE-ART REVIEW

Apoptotic cell death regulation in neurons

fully differentiated into post-mitotic neurons (Fig. 2).

related protease CPP32 in cerebellar granule neurons 233 Ni B, Wu X, Du Y, Su Y, Hamilton-Byrd E, Rockey

You might also like