ISSN 00062979, Biochemistry (Moscow), 2021, Vol. 86, No. 7, pp. 852866. © Pleiades Publishing, Ltd., 2021.

Published in Russian in Biokhimiya, 2021, Vol. 86, No. 7, pp. 10271042.

REVIEW

Cerebral Dopamine Neurotrophic Factor (CDNF):

Structure, Functions, and Therapeutic Potential
Dmitry V. Eremin1, Tatiana V. Ilchibaeva1, and Anton S. Tsybko1,a*

1
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
a
email: antoncybko@mail.ru
Received April 28, 2021
Revised May 29, 2021
Accepted June 6, 2021

Abstract—The cerebral dopamine neurotrophic factor (CDNF) together with the mesencephalic astrocytederived neu
rotrophic factor (MANF) form a unique family of neurotrophic factors (NTFs) structurally and functionally different from
other proteins with neurotrophic activity. CDNF has no receptors on the cell membrane, is localized mainly in the cavity
of endoplasmic reticulum (ER), and its primary function is to regulate ER stress. In addition, CDNF is able to suppress
inflammation and apoptosis. Due to its functions, CDNF has demonstrated outstanding protective and restorative proper
ties in various models of neuropathology associated with ER stress, including Parkinson’s disease (PD). That is why CDNF
already passed clinical trials in patients with PD. However, despite the name, CDNF functions extend far beyond the
dopamine system in the brain. In particular, there are data on participation of CDNF in the maturation and maintenance
of other neurotransmitter systems, regulation of the processes of neuroplasticity and nonmotor behavior. In the present
review, we discuss the features of CDNF structure and functions, its protective and regenerative properties.

DOI: 10.1134/S0006297921070063

Keywords: neurotrophic factors, cerebral dopamine neurotrophic factor CDNF, ER stress, unfolded protein response UPR,
neuroprotection, Parkinson’s disease

INTRODUCTION Brainderived neurotrophic factor (BDNF), neu

Neurotrophic factors (NTFs) comprise a large group
of polypeptides (up to 200 amino acids) that play a key
role in the development and maintenance of structures of
both central and peripheral nervous systems and many
other systems in the organism [1]. They take part in the
regulation of growth, development, differentiation,
migration, and survival of cell populations, as well as in
the processes of their adaptation to external effects.
Evolutionarily, NTFs are very ancient and go back to the
times even before the development of vertebrates [2].
NTFs have been studied since the 1940s, when the
first of them, nerve growth factor (NGF), was discovered.
Abbreviations: 5HT, serotonin or 5hydroxytriptamine; 6
OHDA, 6hydroxydopamine; CDNF, cerebral dopamine neu
rotrophic factor; DA, dopamine; ER, endoplasmic reticulum;
MANF, mesencephalic astrocytederived neurotrophic factor;
MPTP, 1methyl4phenyl1,2,3,6tetrahydropyridine; NTF,
neurotrophic factor; PD, Parkinson’s disease; UPR, unfolded
protein response.
* To whom the correspondence should be addressed.
rotrophins (NT37), and glial cell linederived neu
rotrophic factor (GDNF) are among the most well
known NTFs today. In addition, a diverse group of pro
teins classified as growth factors has neurotrophic activi
ty [3]. All NTFs are secreted by the cell and bind to recep
tors on the plasma membrane, most of which act as tyro
sine kinases or activate them, triggering downstream sig
naling pathways such as the extracellular signalregulated
kinase pathway (Ras/ERK) or the phosphatidylinositol 3
kinase pathway (PI3K/Akt) [4]. These signaling cascades
mediate synapse formation, survival, differentiation, and
neuronal maturation.
The cerebral dopamine neurotrophic factor (CDNF)
together with the mesencephalic astrocytederived neu
rotrophic factor (MANF) form a special family of secret
ed proteins with neurotrophic activity [5, 6]. CDNF got
its name from the ability to protect and restore dopamin
ergic (DA) neurons, demonstrated in two models of
Parkinson’s disease (PD) induced in rodents and non
human primates by 6hydroxydopamine (6OHDA) or 1
methyl4phenyl1,2,3,6tetrahydropyridine (MPTP)
[68]. The observed neurotrophic effects of CDNF on

852
 STRUCTURE, FUNCTIONS, AND THERAPEUTIC POTENTIAL OF CDNF
nigrostrial DA neurons served as the basis for initiation of
the clinical trials in PD patients [9].
CDNF is not found in the embryonic brain and can
be detected in neuronal cells only on the 10th postnatal
day onwards. However, in the adult brain, CDNF is wide
spread – it can be found in IIVI cortex layers, in CA1
and CA3 regions and dentate gyrus of the hippocampus,
locus coeruleus and Purkinje cells of cerebellum [6].
Despite its name, CDNF is also expressed outside the
central nervous system (CNS) and acts both on peripher
al neurons (for example, in the intestine) and on non
neuronal cells, especially in the tissues with high meta
bolic activity [6, 10]. For example, CDNF is most promi
nently expressed in heart, muscle, and brown adipose tis
sue [10].
CDNF is located in the lumen of endoplasmic retic
ulum (ER) and is highly secreted from the cell under
stress. It has a trophic effect on many tissues and cell
types in a secreted form, but it can protect cells from
within the ER. Although CDNF is classified as NTF for
its neuroprotective and restorative effects, it is structural
ly different from any other NTF such as NGF, BDNF, or
GDNF. Furthermore, no receptors on the cell surface
have been identified for CDNF (as well as for MANF). In
this review, we consider the features of CDNF structure
and functions, and how this NTF ensures cell survival
under various pathological conditions in the CNS.
FEATURES OF CDNF STRUCTURE
The structure of CDNF is unique among NTFs. It is
59% similar to MANF in amino acid composition, but
not homologous to other welldescribed NTFs (such as
NGF, BDNF, GDNF), therefore CDNF and MANF
form a unique family of proteins [11]. The Cdnf gene is
conserved among the vertebrates (be it mouse, human, or
Danio rerio), which all have its orthologs [6, 12]. At the
same time, invertebrates such as fruit fly Drosophila
melanogaster, roundworm Caenorhabditis elegans, and
sponge Suberites domuncula have only one orthologous
gene Manf/Cdnf [1315].
CDNF is a relatively small, soluble protein (18
20 kDa) of 187 aa. A globular Nterminus and an
unstructured Cterminus, connected by a flexible bridge,
are identified in the CDNF structure [11, 16, 17]. Unlike
classical NTFs, CDNF does not have a prosequence for
enzymatic activation. At the Nterminus, there is only a
26 amino acid signal peptide sequence required for
translocation into the ER, where this signal peptide is
cleaved. In addition to the signal peptide, the Nterminus
contains a saposinlike (SAPLIP) domain. SAPLIP pro
teins such as granulisin and NKlysine are known for
their ability to interact with membrane lipids. Bai et al.
[18] showed that MANF interacts with sulfatide, a lipid
present in the extracellular leaflet of cell membranes and
BIOCHEMISTRY (Moscow) Vol. 86 No. 7 2021
853
in the extracellular fluid. Despite the structural similarity
to MANF and the presence of the SAPLIP domain,
CDNF has not been shown to bind sulfatide. This can be
explained by the conserved lysine residue K122, which is
present in the human MANF, but this position is occu
pied by leucine in CDNF. The K112L replacement in
MANF significantly reduces its binding to sulfatide in
humans [18]. At the same time, there are data indicating
possible involvement of CDNF in the D. melanogaster
lipid metabolism [19]. The fact that the saposinlike
domain in MANF, but not in CDNF, interacts with
lipids, raises an interesting question about the fundamen
tal differences between these two NTFs. Does CDNF
bind a different set of lipids than MANF, or does it bind
them under different conditions (different pH)? The pos
sible roles of MANF and CDNF in the lipid and mem
brane regulation could be associated with the different
functions they play in maintaining ER homeostasis.
Human CDNF contains Nlinked and Olinked gly
cosylation sites [20, 21]. Glycosylated and nonglycosy
lated forms are found in cells with overexpression of
CDNF [20]. However, it has been shown that glycosyla
tion does not play any role in the CDNF secretion and
neuroprotective activity [6, 21].
CDNF has 2 CXXC motifs, with one located at the
Nterminus and the other at the Cterminus [11]. This
CXXC motif is present in many proteins with antioxidant
properties, such as disulfide isomerases, which are locat
ed in the ER and mediate correct protein folding [22].
Cysteines in the CXXC motif of disulfide isomerases cat
alyze strengthening of disulfide bonds in the substrate
proteins, in addition, ensure their correct folding [22].
Neither CDNF nor MANF show oxidoreductase activity,
but their Cterminal CXXC motifs are required for cyto
protective activity. In particular, it has been shown
recently that the CXXC motif helps MANF to perform
the functions of a chaperone and to facilitate correct fold
ing of proteins in the ER [23]. A similar function can be
expected from CDNF.
The Cterminus of CDNF contains a SAPlike
(SAFA/B, Acinus, PIAS) domain, which is the putative
DNA/RNA binding domain. Function of the SAP
domain in CDNF is still unknown. Although a similar
SAPlike domain of MANF demonstrated binding to the
p65 subunit of the transcription factor NFκB [24] and to
BiP/GRP78 in its ADPbound state, preventing
nucleotide substitution and thus changing the
BiP/GRP78 activity [25].
Cterminus of CDNF is partially unstructured and
contains an ER retention sequence (ERS). Cterminal
tails with ERS, which interact with KDEL receptors,
allow resident proteins to be retained in the ER lumen in
the state of homeostasis [26]. The canonical ERS consists
of a sequence of four amino acids – lysineasparagine
glutamineleucine (“KDEL” in the oneletter code). In
CDNF, this is the KTEL sequence, which could be suffi
854 EREMIN et al.
cient for retention in EPR [27]. The KTEL sequence is
important for regulating CDNF secretion in response to
ER stress associated with the decreased calcium levels
[28]. Removal of ERS at the Cterminus of CDNF led to
its secretion and left cells unprotected to the action of
thapsigargin (ER stress inducer) [29].
Taken together, these data confirm that CDNF is an
ER protein with unique structure and properties, which
greatly distinguishes it from other wellstudied NTFs.
Small structural differences between CDNF and MANF
can, however, significantly affect their functions. This is
evidenced by the data obtained for MANF and CDNF
knockouts. In particular, the MANF knockout animals
(Manf–/–) are characterized with serious growth impair
ments, including development of insulindependent dia
betes [30]. In heterozygous mice with MANF deficiency
(MANFHet), chronic inflammation is observed in many
tissues, as well as steatosis (increased lipid aggregation in
hepatocytes) and liver fibrosis [31]. On the contrary, the
CDNF knockout animals (Cdnf–/–) exhibit good survival,
fertility, and life expectancy, and do not show marked
impairments in development and metabolism [32].
Therefore, not only the structure, but also the functions
of CDNF are not the same as those of MANF, and it
would be a mistake to consider the CDNF biology solely
via extrapolation from MANF. However, the notions on
the CDNF functions have been shaped largely by the
MANF research.
CDNF IN REGULATION OF ER STRESS
Unfolded protein response (UPR). ER is responsible
for many critical functions such as lipid biosynthesis, cal
cium storage, and protein maturation [33]. When a cell is
exposed to various negative impacts, proteostasis is dis
rupted in the ER lumen, which leads to ER stress. The
unfolded protein response (UPR) is an evolutionarily
conserved cellular defense mechanism that can reduce
stress by suppressing protein translation, degradation of
misfolded proteins, and activation of signaling pathways
that lead to the production of molecular chaperones
involved in protein folding [34, 35]. The main regulator of
binding to misfolded proteins in the ER is the binding
immunoglobulin protein (BiP, also known as GRP78)
[36]. When BiP dissociate from UPR “sensors” located in
the ER membrane, three associated signaling pathways
are activated: protein kinase R (PKR)like endoplasmic
reticulum kinase (PERK) signaling, activating transcrip
tion factor 6 (ATF6) signaling, and inositolrequiring
enzyme 1 (IRE1) signaling [35] (Fig. 1). Autophos
phorylation of PERK leads to phosphorylation of eIF2α
[37], which reduces protein translation, but selectively
increases expression of the proteins involved in oxidative
stress, folding, and apoptosis. Thus, PERK mediates
transmission of signals of survival and death [38]. ATF6 is
cleaved in the Golgi apparatus, and its Nterminal
domain is transferred to the nucleus to induce transcrip
tion of chaperones and degradation of proteins associated
with the ER [39]. IRE1 activation induces XBP1 tran
script splicing in the cytoplasm. The “edited” XBP1 pro
tein is transferred into the nucleus, where it induces
expression of the genes responsible for degradation of the
ER proteins (ERAD), as well as chaperones [40] (Fig. 1).
Dysregulation of the UPR is associated with many
pathological conditions such as cancer, diabetes and neu
rodegenerative diseases [41, 42]. Many studies have found
a causal link between the progression of neurodegenera
tive diseases and changes in proteostasis in the ER, char
acterized by increased levels of UPR markers [43].
Expression of CDNF under UPR. Today, it is believed
that Manf is one of the UPR marker genes, along with
Grp78, Perk, and Xbp1 [44], since its expression increases
in response to the treatment of cells with tunicamycin, a
drug that causes disruption of proteostasis in the ER [45],
or upon induction of ER stress with unfolded peptides
[46]. It is still premature to consider Cdnf as a UPR mark
er gene. There is only one work in which increase in the
CDNF expression in primary culture of neurons in
response to tunicamycin was shown [47]. At the same
time, studies on the genetic interaction carried out in
D. melanogaster and C. elegans, which have one
Manf/Cdnf homologue, confirmed that the IRE1/XBP1
pathway is involved in the transcriptional regulation of
Manf and Cdnf [13, 48]. In addition, similarly to MANF,
CDNF secretion decreases in response to overexpression
of GRP78 and KDLER in vitro [49]. All these data indi
cate a fundamental similarity between the mechanisms
regulating expression and secretion of CDNF and
MANF. Therefore, we can expect that the new data will
allow considering Cdnf as a UPR marker gene.
CDNF as UPR modulator. The idea of how CDNF
can regulate UPR has developed largely under the influ
ence of the data obtained during studying MANF. This
NTF not only directly binds to GRP78 [50], but also
blocks the release of ADP and binding of ATP, which
allows stabilization of the GRP78 complex with UPR
“sensors” and prevention of the start of this reaction [25].
It is believed that the mechanism through which CDNF
regulates ER stress is similar to that of MANF, i.e., it
implies stabilization of UPR “sensors” by binding to
GRP78 [9, 44]. Several studies characterize CDNF as a
UPR suppressor. In the study of a rat model of
Alzheimer’s disease, CDNF has been shown to reduce
amyloidβinduced UPR activation in hippocampal neu
rons [51]. CDNF acted similarly in the DA neurons
affected by 6OHDA in the PD model [52]. However, the
function of CDNF in UPR cannot be considered as
exclusively suppressive. Firstly, the Cdnf knockout mice
did not show increased expression of UPR marker genes
in their midbrain [32]. Secondly, Arancibia et al. [29]
reported increase in the expression of UPR marker genes
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 STRUCTURE, FUNCTIONS, AND THERAPEUTIC POTENTIAL OF CDNF 855

Fig. 1. Suggested molecular mechanisms of CDNF neuroprotective action. GRP78 normally interacts with UPR sensors, preventing their
activation. During ER stress GRP78 dissociates from ATF6, IRE1 and PERK, which leads to their activation. ATF6 is transferred to the
Golgi complex, where it is cleaved. Active ATF6 acts as a transcription factor and activates transcription of the chaperones such as GRP78
and of the proapoptotic factors CHOP and XBP1, proteins that regulate apoptosis. IRE1 is activated by dimerization and transautophos
phorylation. Cytoplasmic domain of the activated IRE1 has endoribonuclease activity and removes introns in the XBP1 transcript, resulting
in truncated XBP1s, which acts as a transcription factor. XBP1s activates transcription of the genes responsible for degradation of the ER pro
teins (ERAD), as well as chaperones. Activated PERK in the form of a dimer phosphorylates the translation initiation factor eIF2α, which
leads to the general inhibition of protein translation in the cell. It is likely that CDNF in ER binds to GRP78, stabilizes it, and prevents dis
sociation from ATF6, IRE1, and PERK, due to which they are not activated, and the abovedescribed pathways are not triggered. When the
KDEL receptor (KDELR) does not retain CDNF in the ER, it is secreted to the cytoplasm and blocks phosphorylation of eIF2α. Moreover,
free CDNF binds (probably directly) and blocks the effectors of apoptosis – BAX and caspase 3. CDNF can be secreted into the extracellu
lar space, but the exact mechanism of its interaction with membrane lipids is unknown. In microglial cells, blockade of JNK kinase blocks
expression and secretion of the cytokines (IL1β, IL6, PGE2, TNFα), thereby achieving an antiinflammatory effect. It is worth noting that
JNK blockade can also occur in astrocytes and neuronal cells. (Colored versions of the figures are available in online version of the article and
can be accessed at: https://www.springer.com/journal/10541)

in the HEK293 cells and in the primary neuronal culture
transfected with a plasmid expressing CDNF. At the same
time, overexpression of CDNF reduced apoptosis and the
thapsigargininduced cell death [29]. These data can be
interpreted as evidence of the modulating effect of
CDNF on UPR. Probably, CDNF can either completely
stop the development of UPR or moderately activate it
depending on the form and degree of ER stress. In a mod
erate form, UPR can be beneficial since the expression of
chaperones is triggered through its effectors such as ATF6
and XBP1, which effectively eliminates the consequences
of incorrect protein folding.

BIOCHEMISTRY (Moscow) Vol. 86 No. 7 2021

856 EREMIN et al.
ANTIAPOPTOTIC PROPERTIES OF CDNF
Apoptosis is an important indicator of the degree of
neuronal dysfunction in neurodegenerative diseases [53].
At the same time, it is known that ER stress significantly
increases sensitivity of the cells to apoptosis [54, 55].
CDNF can prevent neuronal degeneration and suppress
apoptosis not only by inhibiting ER stress, but also by
directly modulating pathways involved in apoptosis. It
was shown that survival of the PC12 cells treated with 6
OHDA was dosedependently enhanced by the addition
of CDNF protein to the cell culture [56]. Simultaneously,
the Bcl2/Bax ratio increased and the caspase3 activity
decreased in a dosedependent manner [56]. The exact
mechanism by which CDNF suppresses activity of the
proapoptotic proteins is unknown, but some suggestions
can be made by analogy with MANF. The domain at the
Cterminus of MANF was found to be homologous to the
SAP domain of the Ku70 protein [57], which is inhibitor
of the proapoptotic protein Bax [5860]. It was also
shown that a separately synthesized Cterminus of
MANF, injected into neurons, protected them from the
Baxinduced apoptosis [57]. Although the direct binding
of MANF to Bax has not been proven so far [61], the sig
nificant similarity between the Ctermini of MANF and
CDNF still leaves the possibility of such binding.
However, some other mechanisms could also be involved.
ANTIINFLAMMATORY EFFECTS OF CDNF
There is enough evidence that the cytoprotective
properties of CDNF are closely related to antiinflamma
tory activity. Treatment of a primary culture of rat astro
cytes with tunicamycin led to the increase in mRNA lev
els and secretion of proinflammatory cytokines (IL1β,
TNFα, and IL6), and CDNF overexpression in the
astrocytes before treatment reduced this inflammatory
cytokine response [62]. Subsequently, increase in the
CDNF expression was shown in the primary culture of rat
microglia treated with lipopolysaccharide (LPS) [63].
LPS is a bacterial endotoxin that binds to Tolllike recep
tor 4 (TLR4) on the cell membrane and enhances expres
sion of the proinflammatory cytokines such as PGE2,
IL1β, and TNFα. Recombinant CDNF protein reduced
LPSmediated production of PGE2 and IL1β, and their
toxicity in the rat microglial cells [63]. These effects of
CDNF correlated with the decreased phosphorylation of
cJun Nterminal kinase (JNK), which is one of the first
to be activated by LPS. It was also shown that CDNF
decreased activation of the AKT/Fox01/mTor pathway
with concomitant decrease in the level of extracellular
TNFα in the microglia treated with LPS [64], which also
confirmed the assumption that CDNF could reduce
cytokine secretion. At the same time, CDNF overexpres
sion in the substantia nigra of the rats treated with 6
OHDA attenuated expression of the inflammatory mark
ers (nitrosative stress, gliosis, and IL6), but did not affect
expression of cytokines (for example, TNFα and IL1β) in
the striatum [65]. Thus, the antiinflammatory effect of
CDNF is not based only on the decrease in the expression
of cytokines, but also includes other mechanisms of sup
pression of inflammatory response.
PARTICIPATION OF CDNF
IN THE MATURATION AND MAINTENANCE
OF NEUROMEDIATOR SYSTEMS
Since its discovery, CDNF has been strongly associ
ated with the dopamine system (as reflected in its name).
Indeed, CDNF effectively protected and restored DA
neurons in many PD models [66], and recently it was
shown that CDNF performs a similar function in the
Huntington’s disease model [67]. The expression of Cdnf,
like many key genes of the mouse dopamine system,
changed during the longterm space flight on the Bion
M1 biosatellite [68, 69], which indirectly indicates its
association with the adaptation of DA neurons to micro
gravity conditions. Decrease in the expression of tyrosine
hydroxylase (TH), dopamine transporter (DAT), and
decrease of the DA content in the dopamine neurons of
the submucosal plexus of intestine was observed in the
CDNF (Cdnf–/–) knockout mice, the number of neurons
themselves also significantly decreased with age [70].
Surprisingly, neither the number of DA neurons in the
substantia nigra nor the dopamine metabolism change in
the brain of Cdnf–/– mice [32]. However, the authors of
this study noted the agerelated dysfunctions of the DA
system: the work of DAT was disrupted, Dampheta
mineinduced hyperactivity occurred, which was accom
panied by the increased secretion of dopamine. Taken
together, this indicates abnormalities in the axonal termi
nals of the DA neurons in the striatum of the Cdnf–/– mice
[32]. Interestingly, one study found association between
the lateonset development of PD and the rs7094179
polymorphism in the CDNF gene [71]. Although this
polymorphism, according to the authors of the study, is
probably not functional.
Recent evidence indicates that the effects of CDNF
may not be exclusively limited to the dopamine system.
Thus, a significant decrease in the number of neurons
expressing NO synthase (nNOS) and calcitonin gene
related protein (CGRP), as well as GABAergic neurons
was found in the submucosal area of Cdnf –/– mice [70].
The Cdnf gene knockout Danio rerio fish were char
acterized with hyperactivity and behavioral abnormalities
associated with anxiety, social preferences, and flock
cohesion [72]. These animals also showed decreased com
munication skills and increased susceptibility to seizures,
which may be associated with the deficiency of several
neurotransmitter systems, including DA, GABAergic and
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 STRUCTURE, FUNCTIONS, AND THERAPEUTIC POTENTIAL OF CDNF
histaminergic neurons. Although the level of dopamine in
the brain did not change, abnormalities in the grouping of
DA neurons into clusters were found in the fish deficient
in CDNF. At the same time, the number of histamine
neurons surrounding DA neurons was reduced.
Abnormally low numbers of GABAergic neurons were
found in the hypothalamus, and glutamate decarboxylase
expression decreased throughout the brain of Cdnf knock
out fish [72]. These data suggest that CDNF acts as a gen
eral modulator that regulates neurogenesis and matura
tion of the mediatorspecific types of neurons during
development and throughout adulthood, rather than
being limited to the dopaminergic system alone [70]. In
addition, it has been shown in the study by
Voutilainen et al. [52] that CDNF is able to activate the
PI3KAkt signaling pathway both in vitro and in vivo, even
in the intact brain. Since this signaling pathway is a nec
essary component of the longterm potentiation process
[73, 74], it can be assumed that CDNF is actively involved
in the processes of neuroplasticity associated with learn
ing and memory. The first evidence of this has already
been found. Kemppainen et al. [75] demonstrated that the
injection of CDNF protein or a viral construct providing
its overexpression into the hippocampus improved forma
tion of the longterm spatial memory in mice. The works
carried out by the authors of this review have shown that a
single injection of CDNF protein into the ventricle of the
brain of mice affects associative learning of the animals
even ten days after the injection, while there are changes
in the transcription of a number of genes of the brain sero
tonin (5HT) system, for example, those encoding an
enzyme tryptophan hydroxylase2 and 5hydroxytrypta
mine receptor 2A (5HT2A) [76]. In another study, we
found that induction of CDNF overexpression in the dor
sal hippocampus of rats impairs formation of the condi
tioned fear, which is accompanied by the increased
mRNA levels of the genes encoding cFos, CREB, and 5
HT1B receptor [77]. We also found indirect evidence that
not only CDNF modulates development and function of
the mediator systems, but mediators themselves, through
their receptors, can affect expression of this NTF. For
example, the level of CDNF mRNA in the toxindam
aged striatum expectedly increased in the MPTP mouse
model of PD, however, the mRNA level decreased to the
baseline under the treatment with atypical antipsychotic
drugs, clozapine and quetiapine [78]. Since clozapine and
quetiapine are full or partial antagonists of DA and 5HT
receptors (significant binding to 5HT2A receptors should
be noted), as well as histamine and muscarinic receptors,
it can be assumed that neurotransmitters can also modu
late CDNF expression through these receptors.
Interestingly, modulation by various neurotransmitter sys
tems is one of the characteristic features for the wellstud
ied NTFs such as BDNF and GDNF [79, 80].
The abovementioned facts indicate that, despite
significant structural features and unique mechanism of
BIOCHEMISTRY (Moscow) Vol. 86 No. 7 2021
857
action, CDNF functionally is much closer to the classical
NTF than was initially thought. Even more  today we
have every reason to classify CDNF as a true NTF.
TROPHIC CDNF ACTIVITY
IN NEUROPATHOLOGIES
ASSOCIATED WITH ER STRESS
Changes in the CDNF expression have been
observed in the diseases associated with ER stress, includ
ing cerebral ischemia [20, 47, 81] and PD [82]. Despite
the fact that the data on involvement of CDNF in the
pathogenesis of certain diseases are limited [71, 8385],
the results of numerous trials with various models of neu
ropathology convincingly demonstrate outstanding pro
tective and restorative effects of CDNF (table).
Parkinson’s disease (PD). There is enough evidence
of a significant role of UPR in the pathogenesis of PD
[86]. In the postmortem studies of DA neurons of sub
stantia nigra from PD patients, excessive phosphorylation
of PERK and IRE1 was detected. The same proteins in an
activated form have been found in the neurons with inclu
sions of αsynuclein, which is a key component of the
Lewy bodies, the main neuropathological marker of PD
[8790]. UPR molecular pathways are also activated in
the models of PD induced by toxins (MPTP, 6OHDA)
[9193]. Moreover, the use of the PERK inhibitor
GSK2606414 [90] or overexpression of XBP1 [94] can
result in the significant improvements in experimental
animals. The ability to modulate UPR is a unique prop
erty of CDNF that distinguishes it from other NTFs also
considered as therapeutic agents for PD. When compar
ing CDNF and GDNF in the 6OHDA model, only the
injection of the CDNF protein reduced the ER stress
markers expression [52]. Moreover, the in vitro and in vivo
studies have shown that CDNF can protect DA neurons
from the toxic effect of αsynuclein oligomers [95, 96].
Additionally, it was shown in the recent work by
Albert et al. [96] that CDNF physically binds to αsynu
clein preventing internalization of its fibrils into neurons
and forming insoluble phosphorylated αsynuclein inclu
sions, which prevents formation of toxic oligomers of this
protein. This effect was demonstrated not only in the cul
ture of primary hippocampal neurons, but also in ani
mals. Mice and aged rats were injected acutely or chron
ically with CDNF one month after the injection of α
synuclein fibrils into striatum. Although the number of
THpositive neurons did not increase after that, the ani
mals showed significant improvement in the motor func
tions. It should be noted that such effects on αsynuclein
have not been observed with other NTFs.
To date, a number of CDNF trials have been carried
out using various PD models. It was shown already in the
first of them that unilateral injection of the CDNF pro
tein into the striatum of rats in the 6OHDA model leads
858 EREMIN et al.

CDNF in neuropathology models

Disease Model system Species Function Mechanism Reference

Parkinson’s МРТР rhesus monkey regeneration of DA neurons THpositive cells in SN ↑ Huttunen,

disease and restoration of motor Saarma [9]
functions

6 OHDA marmosets regeneration of DA neurons DAT ↑ Garea

Rodrguez
et al. [8]

6 OHDA rat regeneration of DA neurons THpositive cells in SN ↑ Lindholm et

and restoration of motor al. [6]
functions

6 OHDA rat regeneration of DA neurons THpositive cells in SN ↑; Voutilainen

and restoration of motor THpositive fibroblasts et al. [97]
functions in St ↑

6 OHDA rat protection of DA neurons partial protection of TH Bäck et al.

and restoration of motor positive neurons and fibers [100]
functions in SN and St

6 OHDA rat regeneration of DA neurons THpositive cells in SN ↑; Ren et al.

and restoration of motor THpositive fibers in St ↑; [101]
functions function of DA neurons ↑

6 OHDA rat protection of DA neurons combined overexpression Cordero

and restoration of motor of CDNF and MANF; Llana et al.
functions protection of THpositive [102]
cells; THpositive fibers in
St ↑

6 OHDA rat regeneration of DA neurons expression of ER stress Voutilainen

and restoration of motor markers ↓; THpositive et al. [52]
functions cells in SN ↑; THpositive
fibers in St ↑

6 OHDA rat regeneration of DA neurons THpositive cells in SN ↑ Wang et al.

and restoration of motor with the injection of [105]
functions two but not five AAV8CDNF no more
weeks after injury than two weeks after 6OHDA

6 OHDA rat improving motor function TH in SN ↑ Huotarinen

when combining CDNF et al. [104]
and DBS

МРТР mouse protection and regeneration THpositive cells in SN ↑; Airavaara et

of DA neurons and restora THpositive fibers in St ↑ al. [7]
tion of motor functions

6 OHDA and αsynu mouse DA protection of DA neurons oligomers of αsynuclein ↓ Latge et al.
clein neurons [95]

αsynuclein, hip mouse, rat protection of neurons and oligomers of αsynuclein ↓ Albert et al.
pocampal neurons, restoration of motor func [96]
intrastriatal injection tions
of αsynuclein

МРР+ rat DA neu protection of DA neurons combined action of CDNF Jaumotte et

rons and synthetic neurturin al. [103]
(N4); DAT function ↑

Alzheimer’s APP/PS1 line mouse improving spatial learning not known Kemppainen
disease and memory et al. [75]

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 STRUCTURE, FUNCTIONS, AND THERAPEUTIC POTENTIAL OF CDNF 859

Table (Contd.)

Disease Model system Species Function Mechanism Reference

hippocampal neurons rat protecting cells from β ER stress ↓ Zhou et al.

amyloidinduced synapto [51]
toxicity

Nerve damage transection of the sci rat regeneration of the nerve axon and Schwann cell Cheng et al.
atic nerve and restoration of its func regeneration; myelin layer [62]
tion, prevention of atrophy thickness ↑
of the innervated muscle
tissue

transection of the sci
atic nerve
rat regeneration of the nerve
and restoration of its func
tion, prevention of atrophy
of the innervated muscle
tissue
regeneration of axon and Liu et al.
Schwann cells during trans [110]
plantation of CDNFpro
ducing MSCs; myelin layer
thickness ↑

traumatic spinal cord rat regeneration of nerve neuroinflammation ↓; pro Zhao et al.
injury fibers, restoration of motor inflammatory cytokines ↓; [111]
and sensorimotor functions remyelination and fiber
regeneration during trans
plantation of CDNFpro
ducing MSCs

Ischemia middle cerebral artery rat reduction of the ischemic apoptosis ↓ Zhang et al.
occlusion area and improvement of [47]
motor function

ischemia−reperfusion rat improvement in body no effect on neuronal Anttila et al.

asymmetry indicators and a regeneration and [107]
decrease in scores on the phagocytic activity
Biderson scale

Notes. Designations: 6OHDA, 6hydroxydopamine; MPTP, 1methyl4phenyl1,2,3,6tetrahydropyridine; DA, dopaminergic; TH, tyrosine
hydroxylase; DAT, dopamine transporter; SN, substantia nigra; St, striatum; ER, endoplasmic reticulum; DBS, deep brain stimulation;
MSCs, mesenchymal stem cells.

to the significant restoration of motor functions, protec
tion and regeneration of DA neurons and their axons in
the nigrostrial pathway [6]. A similar effect in the same
PD model was achieved with a twoweek injection of
CDNF into striatum using an osmotic minipump [97]. In
this study GDNF showed only a rather modest effect. It
is also worth noting that CDNF diffused into the tissue
significantly better than GDNF [97]. As it became known
from the study by Mätlik et al. [98], the CDNF protein is
transported with great efficiency retrogradely along the
axons of DA neurons and, after injection into striatum, it
is observed exclusively in their bodies in substantia nigra.
Bilateral injection of CDNF in the striatum 20 h prior or
one week after MPTP in the mouse MPTP model
improved horizontal and vertical motor activity that was
accompanied by the increase in the number of DA neu
rons and their outgrowth in substantia nigra and striatum,
respectively [99]. CDNF overexpression mediated by the
AAV2 vector in the striatum also demonstrated protective
effect on the DA neurons counteracting the toxic effects
of 6OHDA and preventing motor impairments
[100, 101]. One study showed an additive effect of overex
pression of CDNF and MANF in the substantia nigra
[102]. However, the levels of both NTFs after gene thera
py are unknown, and biological activity of these proteins
delivered to neurons using a lentiviral vector is unclear.
Moreover, an additive effect of treatment with the CDNF
protein and a synthetic variant of neurturin (N4) on the
cultured DA neurons from substantia nigra treated with
MPP+ (toxic metabolite MPTP) was shown recent
ly [103].
It is assumed that the therapeutic effects of CDNF
depend on the number of survived DA neurons in the
nigrostrial pathway. In those PD models that try to repro
duce the late stage of PD with significant loss of neurons,
injection of CDNF protein [104] or its overexpression
[105] can achieve only a limited effect.
CDNF has been tested in two primate PD models. In
one study on marmosets (Callithrix jacchus) with unilat
eral injection of 6OHDA, chronic administration of

BIOCHEMISTRY (Moscow) Vol. 86 No. 7 2021

860 EREMIN et al.
CDNF into the lesioned striatum led to the increase in
the radioligand binding to DAT, recorded by positron
emission tomography [8], which indicated restoration of
the terminals of DA neurons. GDNF used as positive
control in this study did not demonstrate any similar
effect [8]. In elderly rhesus monkeys (Macaca mulatta)
with unilateral injection of MPTP, CDNF injections
improved motor functions and restored DA neurons in
the substantia nigra [9].
Toxicological studies of the repeated bilateral injec
tions of recombinant CDNF protein into the striatum of
rhesus monkeys demonstrated complete safety of this
NTF [9]. This made it possible to move on to clinical tri
als on volunteers with PD. A phase III randomized,
placebocontrolled, multicenter study, launched in late
2017, enrolled 18 patients with moderate idiopathic PD
(ClinicalTrials.gov ID NCT03295786) who received
CDNF in striatum monthly for 6 months. The results of
the study, which ended in August 2020, have not yet been
published, however, preliminary data show safety of
CDNF 6 and 12 months after the start of administration,
as well as increase in DAT function and motor functions
of the patients [106].
Ischemia. Compared to MANF, there are only few
studies evaluating protective and restorative properties of
CDNF in the ischemic brain damage. In the rats model of
ischemia caused by occlusion of the middle cerebral
artery, CDNF levels increased in the periinfarction area
after 2 h [47], which directly indicated involvement of
CDNF in eliminating consequences of ER stress.
Moreover, injection of CDNF before occlusion resulted
not only in the decrease of the size of ischemic region and
decrease in apoptosis in it, but also in improvement of the
motor functions of animals [47]. Introduction of CDNF
protein into the thalamus of rats on the 7th day after cor
tical ischemia–reperfusion facilitated functional recov
ery, which was manifested by the improvement of body
asymmetry parameters and decrease in the Bederson’s
score [107]. However, functional improvements were not
accompanied by the restoration of lost neurons and
decrease in phagocytic activity [107].
Alzheimer’s disease (AD). Although most of the stud
ies on CDNF in neurodegenerative diseases focus on PD,
there is evidence that CDNF also has a beneficial effect in
AD models. In the work of Zhou et al. [51] on a primary
culture of rat hippocampal neurons, addition of the
recombinant CDNF protein to the medium reduced the
ER stress induced by βamyloid treatment and protected
cells from βamyloidinduced synaptotoxicity, which is
believed to precede the loss of neurons and coincides with
the cognitive impairments observed in AD.
Extremely interesting results were obtained in the
AD animal model – double transgenic mice APP/PS1
(amyloid precursor protein/presenilin1). This mouse line
is widely used as an AD model. These mice show βamy
loid deposits that build up in brain over time, with signif
icant deposits already visible at the age of 6 months [108].
This is accompanied by the shortterm and longterm
memory impairment [109]. A group of scientists led by
Kemppainen showed in 2015 [75] that introduction of the
recombinant CDNF or AAV2 protein, a construct pro
viding CDNF overexpression, into the hippocampus
improved longterm memory in both APP/PSI mice and
wildtype animals. However, there was no effect on neo
phobia and early stages of spatial learning. Importantly,
improvement in the longterm memory in the APP/PSI
mice was not associated with the decrease in the amyloid
β accumulation or increased neurogenesis in the hip
pocampus [75], suggesting a yet unknown mechanism
through which CDNF affects synaptic plasticity and
memory.
Peripheral nerve damage. Peripheral nerve damage
often leads to axonal degeneration and neuronal loss,
leading to impaired regeneration and severe functional
impairment. Induction of CDNF overexpression in the
rats with transected sciatic nerve using a lentiviral vector
led to significant improvements in the axon and Schwann
cell regeneration, which increased thickness of the myelin
layer [62]. In another study in a similar model, mes
enchymal stem cells were transduced with CDNF using a
lentivirusbased vector and placed in the collagen tubes to
assess their regenerative effects [110]. And again, the
presence of CDNF made it possible to achieve a signifi
cant increase in the regeneration of axons and Schwann
cells, and increased myelination and diameter of the
axons. In both studies, restoration of the cut sciatic nerve,
its function, prevention of atrophy of the innervated mus
cle tissue was observed [62, 110]. Regenerative potential
of CDNF has also been demonstrated in the model of
traumatic spinal cord injury. After the introduction of
mesenchymal stem cells with CDNF overexpression into
the affected area, neuroinflammation was suppressed,
production of the proinflammatory cytokines decreased,
remyelination and regeneration of nerve fibers occurred,
which ultimately led to restoration of the motor and sen
sorimotor functions in animals [111]. Ability of CDNF to
promote regeneration and functional repair of the nerve
fibers makes this NTF a promising treatment for periph
eral nerve and spinal cord injuries, for which no effective
therapy is currently available.
CONCLUSIONS
CDNF has a unique structure and properties that
distinguish it from other NTFs. Therapeutic potential of
CDNF significantly exceeds that of other NTFs due to its
ability to negatively regulate UPR, suppress apoptosis and
inflammation. For example, attempts at the clinical use
of GDNF in the treatment of PD have 20yearlong his
tory, but no significant progress has yet been achieved. On
the contrary, the use of CDNF opens up new possibilities
BIOCHEMISTRY (Moscow) Vol. 86 No. 7 2021
 STRUCTURE, FUNCTIONS, AND THERAPEUTIC POTENTIAL OF CDNF
Fig. 2. Generalized scheme of CDNF effects. The dotted line indicates a hypothetical mechanism.
in the treatment of PD, as well as in the treatment of
other neurological disorders. At the same time, the data
on participation of CDNF in the maturation and func
tioning of not only dopaminergic, but also other neuro
transmitter systems become increasingly available. In
addition, some studies suggest that CDNF is likely to be
involved in controlling complex forms of behavior such as
spatial learning (Fig. 2). There is a reason to believe that,
due to the neurotrophic properties of CDNF, the range of
behaviors it regulates is even wider. The focus of most
studies on the involvement of CDNF in the control of
motor functions is understandable in the context of PD
therapy, however, it is worth expanding the research area,
firstly, because of the possible use of this NTF in the treat
ment of other neuropathologies, and, secondly, for better
understanding of neuroplasticity processes in a healthy
brain from the point of view of fundamental science.
The prospect of clinical application of CDNF dic
tates the need to study the exact mechanisms by which
this NTF regulates neuroplasticity processes, neverthe
less, the already wellknown functions of CDNF require
more thorough research. Recent data show that in some
aspects CDNF and closely related MANF have funda
mental differences (for example, it concerns interactions
with lipids). Therefore, the wellstudied molecular fea
tures of MANF cannot be easily translated into CDNF.
In particular, this is related to the modulating role of
CDNF in the regulation of UPR under various forms of
ER stress. When are the UPR proteins blocked, when are
they activated, and how does this promote neuronal sur
vival? These questions are still awaiting answers.
BIOCHEMISTRY (Moscow) Vol. 86 No. 7 2021
861
Funding. This work was financially supported by the
Russian Science Foundation (grant no. 197500016).
Ethics declarations. The authors declare no conflicts
of interest in financial or any other sphere. This article
does not contain any studies with human participants or
animals performed by any of the authors.
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