Stefanis - 2012 - α-Synuclein in Parkinson's Disease-annotated

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a-Synuclein in Parkinson’s Disease
Leonidas Stefanis
Laboratory of Neurodegenerative Diseases, Biomedical Research Foundation of the Academy
of Athens, and Second Department of Neurology, University of Athens Medical School,
Athens 11527, Greece
Correspondence: lstefanis@bioacademy.gr
a-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropatholog-

ically to Parkinson’s disease (PD). a-Synuclein may contribute to PD pathogenesis in a
number of ways, but it is generally thought that its aberrant soluble oligomeric confor-
mations, termed protofibrils, are the toxic species that mediate disruption of cellular homeo-
stasis and neuronal death, through effects on various intracellular targets, including synaptic
function. Furthermore, secreted a-synuclein may exert deleterious effects on neighboring
cells, including seeding of aggregation, thus possibly contributing to disease propagation.
Although the extent to which a-synuclein is involved in all cases of PD is not clear, targeting
the toxic functions conferred by this protein when it is dysregulated may lead to novel thera-
peutic strategies not only in PD, but also in other neurodegenerative conditions, termed syn-
ucleinopathies.
www.perspectivesinmedicine.org
he first link of Parkinson’s disease (PD) to a- A parallel story that has developed over the
T synuclein was also the first conclusive demon-
stration of a genetic defect leading to PD, and thus
years is the abundant abnormal a-synuclein
pathology that characterizes neuropathological
has historical and conceptual value. Although specimens derived not only from PD patients,
familial contribution to the disease was discussed but also patients with other neurodegenerative
by some, it was felt to be minor at best by most. conditions, collectively termed “synucleinopa-
The tangible discovery of a gene defect linked to thies.” The ability to model abnormal a-synu-
PD in particular families was a ground-breaking clein accumulation in various cellular and
discovery,asitopenedthedoor toafloodof studies animal models has led to the study of the conse-
investigating the genetic base of the disorder, cul- quences of such accumulation, to the decipher-
minating in more recent genome-wide association ing of the molecular pathways involved, and to
studies (GWAS), that, remarkably, have made a full the identification of potential therapeutic tar-
circle back to the origins of the molecular genetic gets. Such targets may prove of general utility,
era of PD; it turns out that one of the major genes and provide the basis for future therapeutics
identified as linked to sporadic PD is none other in most forms of PD, and, potentially, other syn-
than SNCA, the gene encoding for a-synuclein. ucleinopathies.
Editor: Serge Przedborski

Additional Perspectives on Parkinson’s Disease available at www.perspectivesinmedicine.org
Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009399
Cite this article as Cold Spring Harb Perspect Med 2012;4:a009399
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Downloaded from http://perspectivesinmedicine.cshlp.org/ on May 29, 2023 - Published by Cold Spring Harbor Laboratory Press
L. Stefanis
GENETICS OF PD AND OTHER tive risk for sporadic PD in initial association

DISORDERS WITH LINKS TO studies, which were replicated and then con-
SYNUCLEINOPATHIES firmed in a large metanalysis (Maraganore
et al. 2006). Others studies found associations
In 1997, Polymeropoulos et al. reported the of PD with 30 regions of the gene (Mueller et al.
first specific genetic aberration linked to PD 2005; Mizuta et al. 2006). Targeted association
in a large Italian kindred, and in some Greek studies are, however, prone to false positives;
familial cases. The mutation corresponded to a therefore, it is very important that the link of
G209A substitution in the SNCA gene encoding SNCA to sporadic PD has been confirmed
for a-synuclein, resulting in an A53T amino through large unbiased GWAS. SNCA, and, in
acid change. The pattern of inheritance was au- particular, the 30 region, has been a consistent
tosomal-dominant, and the disease was early- hit in such studies, and represents, of the links
onset, usually in the 40s. Although there was identified, probably the most robust one (Nalls
some initial skepticism, based on the fact that et al. 2011).
the threonine was the amino acid in position The conclusion from these genetic studies
53 in the rodent SNCA homolog, this was set is that SNCA is linked to both rare familial
aside following the identification of two more and sporadic PD from a genetic standpoint. It
point mutations in SNCA, leading to A30P is notable that the association of SNCAvariants
and E46K amino acid changes, which were as- to disease has now also been extended to multi-
sociated with autosomal-dominant PD (Kruger ple-system atrophy (MSA), another prototypi-
et al. 1998; Zarranz et al. 2004). The next land- cal synucleinopathy, which is invariably spo-
mark study that linked SNCA to PD through a radic (Al-Chalabi et al. 2009; Scholz et al. 2009).
different mechanism identified triplications of
the SNCA locus in separate families with an au-

tosomal-dominant inheritance pattern (Single- THE INVOLVEMENT OF a-SYNUCLEIN IN
ton et al. 2003). This led to a potential total THE NEUROPATHOLOGICAL PICTURE OF
PD AND RELATED DISORDERS
of a duplication of the a-synuclein load in
such patients, and this was confirmed later The genetic link of SNCA to PD in 1997 led
at the protein level (Miller et al. 2004). Other investigators to rapidly develop appropriate an-
families were subsequently described that har- tibodies against a-synuclein and use them in
bored duplications of the gene, which was histopathological sections of PD patients. a-
similarly associated with autosomal-dominant Synuclein turned out to be robustly expressed
disease (Chartier-Harlin et al. 2004). Interest- within Lewy bodies (LBs), and, in particular,
ingly, a gene dosage effect exists, in that triplica- in the “halo” of the inclusions (Spillantini et al.
tion cases are earlier onset and have a more severe 1997, 1998; Baba et al. 1998). In fact, a-synuclein
course compared to the duplication cases (Fuchs immunohistochemistry is currently the gold
et al. 2007). standard in the neuropathological evaluation
When a specific genetic defect is identified in of PD. With repeated studies, three major in-
rare familial cases, it is almost a reflex reaction to sights emerged: (1) a-synuclein pathology in
look at the same gene in the sporadic disease, PD is not confined to the cell soma, but is also
with the hope of identifying polymorphisms prominent in neuritic processes, (2) it is wide-
that may be linked to the disease in association spread in various brain regions in PD, and (3)
studies. This has not been particularly successful it is present in a number of other synucleinopa-
in other diseases, but in the case of PD and the thies, such as MSA, dementia with Lewy bodies
SNCA gene this approach has borne fruit. Initial (DLBs), many cases of Alzheimer’s disease (AD)
studies focused on the Rep1 polymorphic region (the so-called LB variant of AD), neurodegen-
located approximately 10 kB upstream of the eration with brain iron accumulation (NBIA)
SNCA transcriptional initiation site. Particular type I, pure autonomic failure (PAF), and even
polymorphisms in this region conferred a rela- a subtype of essential tremor (reviewed in Kahle
2 Cite this article as Cold Spring Harb Perspect Med 2012;4:a009399

2008). The distribution of the pathology at the is hoped, will become more widely applicable
cellular and regional level is different in each and available.
disease.
Braak et al. (2003), in their seminal study of
THE STRUCTURE AND FUNCTION OF
the staging of PD pathology, used a-synuclein
a-SYNUCLEIN
immunohistochemistry in a large number of
autopsy cases. Based essentially on a-synuclein The SNCA gene encodes for a 140 amino acid
neuritic pathology (“Lewy neurites”), they sug- protein, which in aqueous solutions does not
gested a six-stage scheme in which the pathol- have a defined structure, hence the term “na-
ogy begins first at the olfactory bulb and the tively unfolded protein.” a-Synuclein, however,
dorsal vagal nucleus and gradually follows an does form a-helical structures on binding to
ascending course, culminating in widespread negatively charged lipids, such as phospholipids
a-synuclein pathology at the later stages, in- present on cellular membranes, and b-sheet-
volving associative cortical regions. Notably, rich structures on prolonged periods of incu-
substantia nigra is only affected in stage 3 of bation. The protein is composed of three dis-
this scheme. Although there have been crit- tinct regions: (1) an amino terminus (residues
icisms against this hypothesis (Burke et al. 1 – 60), containing apolipoprotein lipid-bind-
2008), and it does not explain the absence of ing motifs, which are predicted to form amphi-
clinical symptoms in subjects who on autopsy philic helices conferring the propensity to form
have widespread a-synuclein pathology, or the a-helical structures on membrane binding, (2)
clinical picture of DLB, it appears to hold up a central hydrophobic region (61 –95), so-called
for the majority, but not all, of cases examined NAC (non-Ab component), which confers the
in large cohorts of LB cases (Dickson et al. b-sheet potential, and (3) a carboxyl terminus
2010). What is important to note here is that that is highly negatively charged, and is prone
overall in the PD brain the majority of ab- to be unstructured (Fig. 1). There are at least
normally deposited a-synuclein is in neuritic two shorter alternatively spliced variants of the
processes. The presence of a-synuclein in LBs SNCA gene transcript, but their physiological
is likely the tip of the iceberg. In fact, Kramer and pathological roles have not been well char-
and Shulz-Schaeffer (2007), using a modified acterized (Maroteaux and Scheller 1991; Ueda
protocol termed protein aggregate filtration, et al. 1993; Maroteaux et al. 1988).
showed in DLB cases a remarkable degree of a-Synuclein is a member of the synuclein
aberrant neuritic a-synuclein pathology, in the family of proteins, which also include b- and
virtual absence of LBs. g-synuclein. What largely sets apart a-synuclein
Overall, it is clear that abnormal a-synu- from the other members structurally is the NAC
clein deposition occurs early in PD. Given region. All three members of the family are
the fact that such pathology may develop sec- predominantly neuronal proteins that under
ondarily, for example, owing to iron mishan- physiological conditions localize preferentially
dling in NBIA type I, we cannot be certain to presynaptic terminals (George 2002). There
that it is a primary factor in the disease process. are some reports of extranigral b- and g-synu-
However, the generally quite defined pattern of clein neuritic pathology in synucleinopathies,
a-synuclein pathology in PD, the cellular and but, if it exists, it does not appear to be wide-
animal models of a-synuclein overexpression spread (Galvin et al. 1999). Interestingly, point
that will be discussed, and, most importantly, mutations in b-synuclein have been described
the combination with the genetic data men- in rare cases with DLB (Ohtake et al. 2004),
tioned above, suggest that this aberrant deposi- and expression of one of these in a transgenic
tion is the driving force in PD pathogenesis. mouse model-induced neurodegeneration (Fu-
Such deposition, as mentioned, may be subtle jita et al. 2010). On the other hand, wild-type
and difficult to detect in the absence of elabo- (WT) b-synuclein has been found to be pro-
rate immunohistochemical techniques that, it tective in various settings against a-synuclein-
Cite this article as Cold Spring Harb Perspect Med 2012;4:a009399 3

L. Stefanis
Apolipoprotein motif
Repeat 1 Repeat 2 Repeat 3 Repeat 4 Repeat 5 Repeat 6

Acidic tail
1 140
N C
61 95
A30P A53T
E46K
Mutations genetically
linked to familial
autosomal-dominant
Parkinson’s disease
NAC region necessary for aggregation
Figure 1. Schemtic structure of a-synuclein.
mediated neurodegeneration (Hashimoto et al. modulated in conditions that alter plasticity or

2001; Park and Lansbury, 2003). It would ap- confer injury (George et al. 1995; Kholodilov
pear therefore that WT b-synuclein may have et al. 1999; Vila et al. 2000). Such data have led
neuroprotective properties, but that, under cer- to the notion that a-synuclein may be a modu-
tain situations, it may assume a neurotoxic po- lator of synaptic transmission. Examinations of
tential. neurophysiological properties of mice null for
a-Synuclein is abundantly expressed in the a-synuclein and of cellular systems in which
nervous system, comprising 1% of total cy- WT a-synuclein is overexpressed have been in-
tosolic protein. On immunohistochemistry in strumental in this regard, as they reveal alter-
normal brains a-synuclein antibodies confer ations in neurotransmitter release, which are
a punctuate neuropil staining pattern, consis- not always consistent across neuronal systems
tent with presynaptic terminal staining, whereas (Abeliovich et al. 2000; Murphy et al. 2000;
neuronal soma staining is less apparent (Kahle Cabin et al., 2002; Larsen et al. 2006). Overall
2008). In presynaptic terminals a-synuclein is though, it would appear that a-synuclein acts
present in close proximity, but not within, syn- as a subtle break for neurotransmitter release
aptic vesicles. In fact a-synuclein is also very under circumstances of repeated firing. An ele-
abundant, for unclear reasons, in erythrocytes gant study by Fortin et al. (2005) showed that
and platelets (Barbour et al. 2008). Whether it fluorescently labeled a-synuclein moves away
is expressed at all under physiological condi- from the vesicles on neuronal firing, and then
tions in glia is somewhat controversial; it would gradually returns. These effects may involve
appear that, if it exists, such expression is pre- transient binding of a-synuclein to the vesicles,
sent at very low levels (Mori et al. 2002a). The whereas a-synuclein may also be involved in ve-
expression of a-synuclein is induced during sicular biogenesis, through effects on phospha-
neuronal development, following determina- tidic acid metabolism, and in compartmenta-
tion of neuronal phenotype and establishment lization between resting and readily releasable
of synaptic connections, and lags behind the pools (Murphy et al. 2000). Consistent with a
induction of proteins involved in synaptic role for a-synuclein at the level of synaptic trans-
structure (Withers et al. 1997; Kholodilov et al. mission, a-synuclein modulates profoundly the
1999; Murphy et al. 2000; Rideout et al. 2003). phenotype of mice null for the presynaptic pro-
Moreover, a-synuclein expression levels are tein CSP-a (cysteine string protein-a), which

show synaptic degeneration (Chandra et al. THE AGGREGATION POTENTIAL OF

2005). It is believed that a-synuclein, through a-SYNUCLEIN
a chaperone-like function, may act in synergy
with CSP-a in the assembly of the SNARE com- The ability of a-synuclein to generate b-sheet
plex (Chandra et al. 2005), and this effect may structures under certain circumstances gener-
involve, in particular, binding to synaptotag- ated a lot of enthusiasm, as it provided parallels
min-2 (Burree et al. 2010). to the b-sheet structure of b-amyloid, and con-
Therefore, the main function of a-synuclein sequently, a unified pathogenetic basis for the
would appear to be the control of neurotrans- two most common neurodegenerative diseases.
mitter release, through effects on the SNARE Indeed, WTas well as disease-related mutants of
complex. Recent evidence, to be discussed be- a-synuclein form amyloid-like fibrils on pro-
low, suggests that this physiological function longed incubation in solution (Conway et al.
may provide insight into the aberrant function 2000). It is widely agreed on that such fibrils
unleashed in disease states. form the basis of the mature LBs and Lewy neu-
rites (LNs) present in synucleinopathies. In the
process of fibril formation various intermediate
forms of a-synuclein develop. These are initially
SYNUCLEINOPATHY MODELS
soluble oligomeric forms of a-synuclein that as-
Based on the genetic and pathological data, at- sume spherical, ring-, and stringlike characteris-
tempts have been made to create cellular and tics when seen under the electron microscope.
animal models in which various forms of a- Such structures, collectively termed protofibrils,
synuclein are overexpressed. We have elected gradually become insoluble and coalesce into fi-
to not present such models with any great detail brils. It is difficult to capture these intermediate
here, but rather highlight the inferences gained structures in cells or in vivo, but their biochemi-
from such models regarding the potential cal equivalent isthought to be soluble oligomeric
pathological (and sometimes physiological) ef- forms, some, but not all, of which are SDS-stable
fects of a-synuclein. Suffice it to say here, that and can be detected on SDS/polyacrylamide
there are a number of transgenic mice available, gel electrophoresis (PAGE) gels. Other forms,
in which expression of various forms of a-syn- however, can only be captured on native gels
uclein is achieved through different promoters, or by size-exclusion chromatography (Emma-
allowing in some cases regional and temporal nouilidou et al. 2010a). This cascade of events,
control of expression. In such mice, there is gen- starting from the natively unfolded protein
erally some degree of neurodegneration and LB- and culminating in the mature fibril formation
like pathology, but it does not involve primarily is collectively termed a-synuclein aggregation.
the dopaminergic system. Some mice develop The general consensus in the field is that
behavioral phenotypes that could be akin to aggregation is a main pathogenic feature of a-
presymptomatic PD (reviewed by Chesselet synuclein. This is buttressed by the lack of tox-
2008). An alternative approach has been the icity conferred by WT b-synuclein or by a-syn-
viral-mediated transduction of dopaminergic uclein variants that do not contain the NAC do-
neurons of the substantia nigra of rodents main and do not form aggregates (Periquet et al.
with a-synuclein, and this has been more suc- 2007), by the beneficial effects of overxepressing
cessful in modeling the dopaminergic cell death HSPs, which assist in refolding of aggregation-
aspect of the disease (Kirik et al. 2002). A num- prone proteins, in synucleinopathy models
ber of invertebrate models, including fly (Feany (Auluck and Bonini 2002; Auluck et al. 2002;
and Bender 2000) and Caenorhabditis elegans Klucken et al. 2004), and by the protection con-
(Lasko et al. 2003), have also been created, and ferred in cellular models of a-synuclein overex-
have been very useful in testing theories regard- pression by reagents that inhibit or neutralize
ing the toxic pathways elicited by aberrant a- aggregated species (Vekrellis et al. 2009; Bieschke
synuclein. et al. 2010). However, the protective effects of

L. Stefanis
HSP overexpression are not always apparent or “suck in” essential neuronal components.
(Shimshek et al. 2010). There is less agreement On the other hand, if the protofibril theory
as to which particular species are neurotoxic. is correct, enhancing inclusions could be
A predominant idea is that some of the early viewed as a method to remove the toxic inter-
soluble oligomeric species have such a potential. mediate oligomeric species, and this has been
This is based on the following pieces of data: attempted with some success in cellular
models (Bodner et al. 2006).
(1) A53T and A30P a-synuclein form more
protofibrils than the WT protein, whereas
a-SYNUCLEIN POSTTRANSLATIONAL
only A53T forms more readily mature fi-
MODIFICATIONS AND INTERACTIONS
brils; however, E46K a-synuclein forms
less protofibrils than the WT, therefore a-Synuclein may be modified by phosphoryla-
there is no simple correlation that can ex- tion, oxidation, nitrosylation, glycation, or gly-
plain everything using this scheme, which cosylation. Of all such modifications, the best
is based on in vitro cell-free systems (Con- studied is phosphorylation. Antibodies specific
way et al. 2000; Fredenburg et al. 2007). to S129-phosphorylated a-synuclein promi-
nently decorate LBs in synucleinopathies (Fuji-
(2) Dopamine and its metabolites act as inhib-
wara et al. 2002). Although the initial idea,
itors of the conversion of protofibrils to
which appeared to be buttressed by experiments
mature fibrils in vitro and in vivo, presum-
in transgenic flies, was that such phosphoryla-
ably through the formation of dopamine/
tion enhanced a-synuclein-soluble oligomers
a-synuclein adducts (Conway et al. 2001;
(but actually decreased a-synuclein inclusions)
Mazzulli et al. 2006; Tsika et al. 2010), sug-
and neurotoxicity (Chen et al. 2005, 2009);
gesting that the preferential vulnerability of

subsequent studies have cast doubt on this no-
dopaminergic neurons to the pathogenic
tion, providing contradictory results (Gorba-
process of PD may be attributable to the
tyuk et al. 2008; Paleologou et al. 2008; Azeredo
enhanced presence of soluble oligomers
da Silveira et al. 2009). In fact, it may be that
(although, surprisingly, mouse nigral neu-
S129 phosphorylation, which occurs minimally
rons, which contain more oligomers, ap-
under physiological circumstances, occurs after
pear relatively resistant to transgenic a-
the fact in already formed LBs (Paleologou et al.
synuclein-mediated neurodegeneration).
2008). Enhancing a-synuclein phosphatase ac-
(3) In cellular systems and in vivo, the presence tivity was, however, protective against a-synu-
of soluble oligomers, and not frank inclu- clein-mediated neurotoxicity, suggesting a causal
sions, generally correlates best with neu- detrimental role of a-synuclein phosphorylation
rotoxicity (Gosavi et al. 2002; Lo Bianco in the disease process (Lee et al. 2011). Polo-like
et al. 2002). Two major studies provided kinases appear to be the physiological kinases
support to this idea, as they showed en- for a-synuclein S129 phosphorylation (Inglis
hanced neurotoxicity both in cell culture et al. 2009; Mbefo et al. 2010). S87 is another
and in vivo with artificial mutants of a- phosphorylation site for a-synuclein, and S87-P
synuclein that favored the formation of sol- a-synuclein is also apparent within LBs, but its
uble oligomers over mature fibrils (Karpinar pathological significance is unclear (Paleologou
et al. 2009; Winner et al. 2011). It should et al. 2010). Phosphorylation on a-synuclein ty-
be noted, however, that the issue is not rosine residues has also been reported and may
settled; the protofibrils are heterogeneous, act in opposing fashion to S129 phosphorylation,
“off pathway” oligomers that do not lead at least in Drosophila (Chen et al. 2009).
to toxicity may exist, and frank inclusions A number of studies in cell-free systems
have the potential of being neurotoxic them- and in cell culture have shown that a-synuclein
selves over time, especially if present in axons, can be oxidized, and this seems to drive its oli-
where they can block neuronal trafficking gomerization (Lee et al. 2002; Betarbet et al.

2006; Mirzaei et al. 2006; Qin et al. 2007). Iron tion (Kim et al. 2002; Murray et al. 2003). Calpain,
and dopamine appear to exert a similar effect, one of the enzymes thought to perform such
although whether this is a direct interaction or processing, is especially interesting given its cal-
mediated by oxidation is less clear (Ostrerova- cium dependence and localization at presynaptic
Golts et al. 2000; Conway et al. 2001; Kostka terminals (Mishizen-Eberz et al. 2003, 2005).
et al. 2008; Leong et al. 2009). The potent oxi- a-Synuclein is quite promiscuous in its
dant 4-hydroxy-2-nonenal (HNE) promoted binding properties, and may bind various pro-
stable soluble oligomers, inhibiting their con- teins in neuronal cells, including components
version to fibrils; such stable soluble oligomers of dopamine metabolism, such as tyrosine hy-
were highly toxic, favoring again the soluble droxylase (TH) and the dopamine transporter
oligomer toxicity theory (Qin et al. 2007). In a (DAT), modulating their function (Ostrerova
similar vein, nitration of a-synuclein has been et al. 1999; Perez et al. 2002; Wersinger and
reported; in fact, an antibody specifically gener- Sidhu 2003; Wersinger et al. 2003; Peng et al.
ated against nitrosylated a-synucelin decorates 2005). There are quite a few reports suggesting
LB-like pathology (Giasson et al. 2000). Mono- that through such binding to various proteins,
meric and dimeric nitrated a-synuclein pro- a-synuclein may exert pro- or antiapoptotic
moted fibril formation (Hodara et al. 2004), effects (Ostrerova et al. 1999; da Costa et al.
whereas oligomeric nitrated a-synuclein actu- 2000; Jin et al. 2011), although no effect on pro-
ally inhibited it, stabilizing as soluble oligomers grammed neuronal cell death has been shown in
(Uversky et al. 2005), suggesting complex effects mice null for a-synuclein (Stefanis et al. 2004).
of nitrosylation on a-synuclein aggregation. As Interestingly, however, these mice are resistant
with S129 phosphorylation, it is possible that to the well-known mitochondrial neurotoxin
the intense nitrosylation of a-synuclein within MPTP, through mechanisms that are still not
LB-like structures occurs after the fact. deciphered, but may involve steps both up-
Given the fact that oxidative/nitrative stress stream of and downstream from mitochon-
induced by environmental factors, including drial dysfunction (Dauer et al. 2002). Such mice
mitochondrial toxins, has been heavily impli- are also resistant against neuroinflammation-
cated in PD, oxidation- or nitration-induced induced nigral degeneration conferred by lipo-
a-synuclein oligomerization has attracted at- polysaccharide (LPS) (Gao et al. 2008), suggest-
tention, as a point of potential convergence being that endogenous a-synuclein is somehow
tween environmental and genetic factors lead- involved in such death pathways.
ing to the disease. It should be noted, however, A number of interactions of a-synuclein with
that a-synuclein aggregation could be dissoci- other proteins have been implicated in its aggrega-
ated from mitochondrial toxicity-induced death tion potential; most notable amongst these is syn-
(Liu et al. 2008), arguing against simplistic lin- philin-1, a protein identified through a yeast-
ear pathways to neurodegeneration, and raising two-hybrid screen as an AS-interacting protein,
the issue whether in certain instances the ab- which promotes a-synuclein aggregation and
undant a-synuclein-related pathology may be inclusion formation (Engelender et al. 1999). In-
an epiphenomenon, and not causally related to terestingly, transgenic expression of synphilin-1
neuronal dysfunction and death. Similar infer- on the background of A53T a-synuclein trans-
ences can be taken from a study in proteasomal genic mice attenuates neurodegeneration, as as-
inhibitor-treated neurons, where the b-sheet- sessed by indices of cell death and gliosis, while
like pathology of a-synuclein was dissociated enhancing inclusion formation, suggesting that
from death (Rideout et al. 2004). promoting a-synuclein inclusion formation is
Another modification that may be impor- neuroprotective (Smith et al. 2010).
tant is carboxy-terminal truncation of a-synu- Interactions of a-synuclein with lipids may
clein, leading to fragments lacking part or the be important not only for their physiologic
whole of the acidic tail (Li et al. 2005). These functions, but also for their aberrant effects. Re-
fragments appear to be more prone to fibrilliza- garding the former, it is interesting to note that

L. Stefanis
sequestration of the fatty acid arachidonic acid associated a-synuclein increase was robust in
away from the SNARE complex by a-synuclein vulnerable brain regions (Tong et al. 2010). It
has been suggested to underlie its inhibitory may of course be that neurons with the highest
effect on neuronal transmission (Darios et al. expression levels of a-synuclein are most vulner-
2010), and that alterations in levels of key en- able and succumb early in the disease process,
zymes in lipid signaling, such as PLD2 and giving their place to glia, thus confounding the
PLA2, may underlie the phenotype in SNCA results. To partly circumvent this issue, Gründe-
null microglia, which are overreactive but lack mann et al. (2008) performed laser-capture mi-
phagocytic potential (Austin et al. 2006, 2011). crodissection studies, and reported a consider-
Regarding the latter, polyunsaturated fatty acids able increase of SNCA expression in surviving
(PUFAs) have been shown to enhance oligome- nigral neurons derived from PD brains com-
rization and neurotoxicity of a-synuclein (Per- pared with controls. However, this increase did
rin et al. 2001; Sharon et al. 2003; Assayag et al. not appear to be specific for SNCA (Gründe-
2007). mann et al. 2008). Therefore, the issue is still
open.
An indirect way of approaching this is by
GAIN-OF-FUNCTION AND
assessing whether polymorphic SNCA variants
ACCUMULATION OF a-SYNUCLEIN
that confer disease risk in association studies
The notion that enhanced a-synuclein levels are alter a-synuclein levels in model systems. In
causative in PD pathogenesis is derived from initial studies, the Rep1 polymorphism associ-
the familial SNCA multiplication cases show- ated with the disease led to increased SNCA
ing a dose-dependent correlation of a-synuclein transcriptional activity in neuronal cell lines
load to the PD phenotype, the autosomal-dom- (Chiba-Falek and Nussbaum 2001); this finding
inant pattern of inheritance for the point muta- has been confirmed in mice (Cronin et al.
tions, the accumulation of a-synuclein in synu- 2009), and even in the human brain (Linnertz
cleinopathy brains, and the demonstration that et al. 2009), although in another study an asso-
features of the disease can be mimicked by WT ciation between Rep1 polymorphisms and a-
a-synuclein overexpression in various models. synuclein mRNA and protein levels in the brain
Consistent with this idea, a-synuclein protein was not apparent (Fuchs et al. 2008). Polymor-
levels are increased with aging in the substantia phisms within the 30 region may also correlate
nigra, and correlate with decreased TH immu- with AS levels (Fuchs et al. 2008; Mata et al.
nostaining (Chu and Kordower 2007). How- 2010). Intriguingly, it was reported that risk-
ever, it should be noted that there is insufficient conferring alleles at the 30 untranslated region
evidence that there is a generalized excess of (UTR) were associated with increased expres-
a-synuclein in PD brains. In fact, mRNA stud- sion of an alternatively spliced form of SNCA
ies have been quite contradictory in this regard, (McCarthy et al. 2011), suggesting another me-
with some even showing a decrease of SNCA ex- chanism through which gene variations may be
pression in PD nigra (Dachsel et al. 2007). Pro- linked to the disease.
tein levels are not obviously increased overall in It is generally assumed that a-synuclein leads
PD brains, although clearly there is induction of to disease through a toxic gain-of-function that
insoluble components, including monomeric is likely inherent in the normal protein when it ex-
and oligomeric species. A comprehensive study ceeds a certain level. In apparent agreement with
of multiple brain areas showed that membrane- this, a-synuclein null mice, in contrast to trans-
associated monomeric a-synuclein levels were genic overexpressors, display no overt neuropa-
only modestly increased in the substantia nigra, thological or behavioral phenotype (Abeliovich
and not in other brain regions, of PD patients et al. 2000; Cabin et al. 2002). However, when
compared to controls; even so, the levels in studied more closely, such mice do have some
some PD cases were within the spectrum of con- deficits in the dopaminergic system, in par-
trol values. In contrast, in MSA, the membrane- ticular, a slightly reduced number of postnatal

dopaminergic neurons (Robertson et al. 2004), (2010) found that the WT allele is induced in a
and a drop of dopaminergic terminals with ag- compensatory fashion, and that the total level
ing (Al-Wandi et al. 2010). Thus, the theory that of SNCA messenger RNA (mRNA) exceeds that
part of the PD phenotype might be attributable of controls, suggesting that total SNCA levels,
to the sequestering of physiological a-synuclein rather than the presence of the A53T mutant,
in inclusions, which could cause neuronal, and, are responsible for the disease in these cases.
in particular (in view of the normal function of Although this study was based on a single pa-
the protein), synaptic damage, cannot be dis- tient, it does bring up again the issue of total
carded. SNCA levels as the major determinant of toxicity.
Despite the fact that transcriptional regu- In view of the above, a reasonable avenue to
lation of a-synuclein is so important for PD attack synucleinopathies may be the lowering
pathogenesis, little is known about the mecha- of a-synuclein levels. A note of caution is in or-
nisms involved. Transcription factors GATA-1 der here, given the uncertainty about potential
(Scherzer et al. 2008) and ZSCAN21 (Clough neurotoxicity associated with severe reduction
and Stefanis 2007; Clough et al. 2009) within of a-synuclein levels, as mentioned above. In
Intron 1 have been proposed to play a role as fact, Gorbatyuk et al. (2010) found that siRNA-
inducers of transcription. In the latter case, a mediated down-regulation of a-synuclein led
signaling pathway involving ERK/PI3 kinase to quite considerable neurotoxicity within the
signaling mediated ZSCAN-induced SNCA rat nigral dopaminergic system within a period
transcriptional activation (Clough and Stefanis of 4 wk. In contrast, no toxicity was observed
2007; Clough et al. 2009). A similar ERK-de- when small interfering RNAs (siRNAs) against
pendent signaling pathway regulating SNCA a-synuclein were injected directly into the mon-
production was apparent in enteric neurons key nigra, achieving 50% – 60% down-regula-
(Paillusson et al. 2010). Methylation may be tion of expression (McCormack et al. 2010).
important in SNCA expression, as methylation Control of a-synuclein levels can also be
within Intron 1 suppressed SNCA transcrip- achieved at the level of its degradation. a-Synu-
tional activity, and brains of patients with LB clein degradation has been controversial, but it
diseases showed decreased methylation within appears that the bulk of degradation of at least
this region, suggesting epigenetic regulation of monomeric WT a-synuclein in neuronal cell
SNCA expression (Jowaed et al. 2010; Matsu- systems occurs through the lysosomal pathways
moto et al. 2010). In one study, it was proposed of chaperone-mediated autophagy (CMA) and
that sequestration of the methylation factor macroautophagy (Paxinou et al. 2001; Webb
Dnmt1 away from the nucleus by a-synuclein et al. 2003; Cuervo et al. 2004; Lee et al. 2004;
may lead to reduced methylation and enhanced Vogiatzi et al. 2008; Mak et al. 2010). It has
SNCA exression, thus creating a feed-forward been proposed that dysfunction of these degra-
loop of SNCA overexpression (Desplats et al. dation pathways may be a contributing factor
2011). Posttranscriptional regulation of a-syn- to PD pathogenesis (Xilouri et al. 2008). a-Syn-
uclein can also occur through endogenous uclein may also be turned over by the protea-
micro RNAs, which bind to the 30 end of the some in other experimental settings (Tofaris
gene (Junn et al. 2009; Doxakis 2010). A partic- et al. 2001; Webb et al. 2003). A factor that
ularly interesting twist to the effects of familial may play a role is the exact species of a-synuclein
point mutations in SNCA has been provided studied. In any case, strategies directed toward
by a series of studies that, somewhat counterin- promoting such endogenous degradation sys-
tuitively, suggest that the expression of the mu- tems to enhance clearance of excess a-synuclein
tant alleles is suppressed, especially in cases with have the advantage that they could also alleviate
prolonged disease (Markopoulou et al. 1999; the aberrant effects of a-synuclein on their func-
Kobayashi et al. 2003), through a mechanism tion (see below). Indeed, stimulation of macro-
that may involve histone modifications (Vout- autophagy through pharmacological or molecu-
sinas et al. 2010). Remarkably, Voutsinas et al. lar means leads to increased WT a-synuclein

L. Stefanis
clearance and neuroprotection (Webb et al. induced death (Mosharov et al. 2006). Excess
2003; Spencer et al. 2009). Another attractive intracellular calcium enhanced cytosolic dopa-
method of enhancing clearance of a-synuclein mine, and AS was required for death induced
through the lysosomal pathway may be through by excess dopamine, creating a possible scenario
immunization (Masliah et al. 2005, 2011). in which intracellular calcium, cystolic dopa-
mine, and a-synuclein interact with each other
in a self-feeding cascade leading to neurodegen-
POTENTIAL PATHOGENIC EFFECTS OF
eration (Mosharov et al. 2009). Another factor
a-SYNUCLEIN: a-SYNUCLEIN AT THE
that could be important in this setting is cal-
SYNAPSE
cium-mediated calpain activation that could
Given the physiological role of a-synuclein at lead, as mentioned, to carboxy-terminal a-syn-
the synapse, it is not surprising that studies uclein truncation, consequent oligomerization,
have identified synaptic effects as significant de- and further calcium influx, creating a vicious
terminants of a-synuclein-induced neurotoxic- cycle.
ity in cell culture and in vivo models based on
overexpression of the protein; in some of these
a-SYNUCLEIN AT THE CYTOSKELETON
cases levels of overexpression are modest, ex-
pected to be present in at least the brains of a-Synuclein may impact cytoskeletal dynamics.
the SNCA multiplication cases. The effects Most of the evidence suggests an association of
seen include loss of presynaptic proteins, de- a-synuclein with microtubules. Various investi-
crease of neurotransmitter release, redistribu- gators have detected an interaction of a-synu-
tion of SNARE proteins, enlargement of synap- clein with tubulin (Alim et al. 2002; Zhou
tic vesicles, and inhibition of synaptic vesicle et al. 2010), but the effects reported on tubulin
recycling (Chung et al. 2009; Garcia-Reitböck polymerization are conflicting, with others re-
et al. 2010; Nemani et al. 2010; Scott et al. porting enhanced (Alim et al. 2004; Lin et al.
2010). It is likely that such deficits precede overt 2009), and others reduced (Lee et al. 2006;
neuropathology and are causal in synaptic and Zhou et al. 2010) tubulin polymerization as a
neuritic degeneration, although the sequence result of a-synuclein overexpression. Further-
of synaptic events and the identification of the more, tubulin depolymerization may lead to
exact point in the cascade in which aberrant impaired maturation of a-synuclein protofi-
a-synuclein assumes its neurotoxic potential brils into mature fibrils, which may lead to
are still elusive. enhanced neurotoxicity (Lee and Lee 2002).
Given the role of calcium is presynaptic sig- Another factor that may be important is the re-
naling events, it is tempting to speculate that lationship of a-synuclein to tau, which is likely
perturbations in calcium homeostasis may important in the pathogenesis of sporadic dis-
play a role in the neuritic degeneration induced ease, as in GWAS the two corresponding genes
by a-synuclein. Indeed, there is some evidence are the ones showing the highest association
for this, albeit still somewhat fragmentary, to PD (Nalls et al. 2011). Although tauopathy
implicating primarily a-synuclein oligomers, is not a prominent feature in PD, it is appreci-
which could form pores on cellular membranes ated in certain cases (Kotzbauer et al. 2004).
or alter the properties of voltage-gated recep- In such cases, a-synuclein and tau pathology
tors, leading to excess calcium influx (Volles may occur in the same cell, but the formed ag-
and Lansbury 2002; Danzer et al. 2007; Hettiar- gregates are separate. In fact, each one of these
achchi et al. 2009). Through a similar porelike two proteins has the tendency to seed the aggre-
mechanism, oligomeric AS may also attack syn- gation of the other (Giasson et al. 2003). a-Syn-
aptic vesicles, leading to leakage of neurotrans- uclein appears to enhance tau phosphorylation,
mitter in the cytosol; in the case of dopamine and this may lead to secondary effects on the
vesicles, this would mean excess cytosolic dop- microtubular network (Jensen et al. 1999; Hag-
amine, which could lead to oxidative stress- gerty et al. 2011; Qureshi and Paudel 2011).

Furthermore, a-synuclein may bind and in- compensatory macroautophagy induction that
fluence polymerization of actin, and thus per- may be detrimental to neuronal survival (Xi-
haps indirectly affect cellular trafficking and louri et al. 2009). The issue is, however, contro-
synaptic function; disparate effects on actin versial, as others find that WT a-synuclein ac-
were observed between WT and A30P mutant tually diminishes macroautophagy, through an
a-synuclein (Sousa et al. 2009). Another aspect inhibitory action at the level of phagophore for-
that appears to be affected by aberrant a-synu- mation (Winslow et al. 2010).
clein, and may be related to the effects on the An interesting issue that relates to a-synu-
cytoskeleton, is axonal transport. In an adeno- clein degradation and its effects on protein deg-
associated virus (AAV) model of nigral synu- radation systems is the relationship of PD to
cleinopathy, early changes before cell death Gaucher disease and glucocerebrosidase (GBA).
included a diminution at the level of the stria- Heterozygote and homozygote carriers of GBA
tum of motor proteins involved in anterograde mutations are at an increased risk of develop-
transport, and an increase of those involved in ing PD. It is controversial whether this repre-
retrograde transport (Chung et al. 2009). sents a loss-of-function of GBA or a gain-of-
function conferred by the mutants. According
to some, loss-of-function of GBA is sufficient
a-SYNUCLEIN AND PROTEIN
to induce a-synuclein accumulation and aggre-
DEGRADATION SYSTEMS
gation (Manning-Bog et al. 2010; Mazzulli et al.
An issue that has attracted a lot of attention is the 2011; Xu et al. 2011), which may occur second-
possibility that aberrant a-synuclein may im- ary to lysosomal dysfunction (Mazzulli et al.
pact protein degradation systems. This notion 2011); others find that a-synuclein accumulates
is attractive, as a number of neurodegenerative only on overexpression of GBA mutants, favor-
conditions are associated with impairments of ing a gain of toxic function mechanism (Cullen
protein clearance, and such impairments have et al. 2011). The accumulation of substrates
the potential to create a vicious loop involving such as glycosylceramide owing to GBA loss-
aberrant a-synuclein accumulation. Aberrant of-function may also confer increased tendency
a-synuclein, mutant, or under certain circum- of a-synuclein to oligomerize (Mazzulli et al.
stances, WT, can induce proteasomal dysfunc- 2011; Xu et al. 2011); on the other hand, oligo-
tion in a number of cell-free, cellular, and in meric a-synuclein may impact on GBA, leading
vivo settings (Stefanis et al. 2001; Tanaka et al. to its dysfunction, creating a vicious cycle of ly-
2001; Petrucelli et al. 2002; Snyder et al. 2003), sosomal dysfunction and aberrant a-synuclein
although this is not universally observed (Mar- accumulation (Mazzulli et al. 2011).
tin-Clemente et al. 2004). It is thought that oli-
gomeric a-synuclein, and, in particular, small
a-SYNUCLEIN AT THE MITOCHONDRIA
soluble oligomeric forms that are themselves de-
AND RELATIONSHIP TO OXIDATIVE
graded by the proteasome, may exert this effect
STRESS
(Lindersson et al. 2004; Emmanouilidou et al.
2010a). This would create the potential for the Many studies now have confirmed that a pro-
vicious cycle mentioned above. portion of a-synuclein, endogenous or overex-
Mutant a-synuclein may also aberrantly pressed, resides within mitochondria, and that
impact the lysosomes, causing impairment of it causes down-regulation of complex I activity,
CMA (Cuervo et al. 2004; Xilouri et al. 2009; thus linking a-synuclein with the effects of mi-
Alvarez-Erviti et al. 2010). WTAS, in an adduct tochondrial toxins, and potentially, sporadic
with dopamine, can cause a similar effect (Mar- PD (Li et al. 2007; Devi et al. 2008; Nakamura
tinez-Vicente et al. 2008). Interestingly, the main et al. 2008; Liu et al. 2009; Loeb et al. 2010).
proteins involved in CMA, Lamp2a and Hsc70, Furthermore, brain mitochondria morphology
are diminished in PD brains (Alvarez-Erviti is disrupted in a-synuclein transgenic mice
et al. 2010). Such CMA impairment may cause (Martin et al. 2006). a-Synuclein, potentially

L. Stefanis
in the form of small oligomers, appears to mediated toxicity in a variety of cellular and in
induce mitochondrial fragmentation, which vivo models. Thayanidhi et al. (2010) suggested
may be responsible for subsequent mitochon- that in mammalian systems the ER/Golgi transi-
drial dysfunction and death (Kamp et al. 2010, tion was delayed owing to an antagonistic effect
Nakamura et al. 2011). a-Synuclein, and espe- of a-synuclein on ER/Golgi SNAREs. Over-
cially the mutant form, perhaps through the expression of other Rabs, more closely linked
same mechanism of fragmentation, also in- to synaptic vesicular function, such as Rab3A,
duces inappropriate excessive mitophagy, which also prevented dopaminergic toxicity in the a-
leads to mitochondrial removal and neuronal synuclein C. elegans model, suggesting that these
death (Choubey et al. 2011). Interestingly, en- phenomena may more broadly reflect the inter-
hancing the expression of PGC-1a, the master action and effects of a-synuclein on vesicular
transcriptional regulator of nuclearly encoded dynamics (Gitler et al. 2008).
mitochondrial subunits, which is down-regu-
lated in PD brains, leads to protection against
a-SYNUCLEIN IN THE NUCLEUS
a-synuclein-induced neurodegeneration in cel-
lular models (Zheng et al. 2010). Synuclein bears its name from its apparent lo-
Through such effects on mitochondria, and calization in the nucleus and presynatic nerve
especially the complex I inhibition, a-synuclein terminals (Maroteaux et al. 1988). However,
could potentially induce reactive oxygen species nuclear localization of a-synuclein has only
(ROS) production, oxidative stress, and resultant been observed inconsistently (Mori et al.
neuronal death. There is in fact some evidence 2002b; Yu et al. 2007); it actually appears that,
that a-synuclein overexpression can induce ROS, at least in transgenic mice, a-synuclein phos-
and that suppressing these through molec- phorylated at S129 may be preferentially local-
ular or pharmacological means may be neuro- ized in the nucleus (Schell et al. 2009). a-Synu-
protective in mammalian (Hsu et al. 2000; Clark clein has been found to interact with histones
et al. 2010; Liu et al. 2011) or insect systems on nuclear translocation in nigral neurons in re-
(Wassef et al. 2007; Botella et al. 2008). sponse to the herbicide paraquat (Goers et al.
2003), and to reduce histone acetylation (Kon-
topoulos et al. 2006). Inhibitors of histone de-
a-SYNUCLEIN AT THE ER/GOLGI
acetylase (HDAC) rescued a-synuclein-medi-
In a neuronal cell model based on adenoviral ated neurotoxicity in cell culture and in vivo
expression of a-synuclein, Golgi fragmentation Drosophila models (Kontopoulos et al. 2006).
was an early feature and correlated with the ap- Furthermore, inhibition of Sirtuin 2, a mamma-
pearance of soluble oligomeric species (Gosavi lian HDAC, which led to increased acetylation,
et al. 2002). Smith et al. (2005) observed endo- was associated with neuroprotection in various
plasmic reticulum (ER) stress as an early event models of synucleinopathy, although whether
in an inducible model of A53T a-synuclein- potential acetylation effects on histone were in-
mediated neurotoxicity, and were able to inhibit volved was not ascertained (Outeiro et al. 2007).
death using a pharmacological inhibitor of ER
stress, also suggesting that a primary target of
a-SYNUCLEIN OUTSIDE THE CELL:
a-synuclein may be the ER/Golgi. In a blinded
THE THEORY OF PROPAGATION
screen in a yeast model, the major class of modu-
lators of a-synuclein toxicity was genes involved Although initially a-synuclein was thought to
in vesicular trafficking (Willingham et al. 2003). be a purely intracellular protein, as it lacks a sig-
This was taken one step further by Cooper et al. naling sequence that would direct it to the secre-
(2006), who identified ER-to-Golgi trafficking tory pathway, it gradually became clear that it
as the major cellular perturbation in this yeast could be detected in the conditioned medium
model, and Rab1, a protein involved in this tran- of cells and in extracellular fluids, such as
sition, as a critical determinant of a-synuclein- plasma and CSF (El-Agnaf et al. 2003; Lee

et al. 2005). The mechanism of a-synuclein se- (Desplats et al. 2009), and fetal dopaminergic
cretion is not well understood, but it appears to neurons also showed uptake of host a-synuclein
occur through a nonclassical secretory pathway (Hansen et al. 2011); on the other, fetal dopami-
(Lee et al. 2005), possibly within exosomes, en- nergic grafts in humans showed LB pathology
docytic vesicles that are contained within mul- many years after implantation, although wheth-
tivesicular bodies and are released on calcium er the a-synuclein within the grafted neurons
influx (Emmanouilidou et al. 2010b). The exis- was host-derived could not be determined with
tence of extracellular a-synuclein in rodent and certainty (Kordower et al. 2008). An intriguing
human brain interstitial fluid has been con- study has brought together the mitochondrial
firmed by microdialysis (Emmanouilidou et al. dysfunction with the a-synuclein propagation
2011). Importantly, secreted a-synuclein can theories. Intragastric administration of the com-
impact neuronal homeostasis and lead to neu- plex I inhibitor rotenone led to enteric a-synu-
ronal death, even at concentrations close to clein pathology, which gradually spread to the
those identified in bodily fluids, and the respon- central nervous system (CNS), including dopa-
sible species, at least in part, appear to be soluble minergic neurons, and caused delayed neuro-
oligomeric (Emmanouilidou et al. 2010b; Dan- toxicity, suggesting that, once initiated by mito-
zer et al. 2011). Furthermore, various reports chondrial dysfunction, a-synuclein aberrant
have shown that extracellular a-synuclein can conformations assume an independent propa-
induce inflammatory reactions in glial cells, gating seeding and neurotoxic potential (Pan-
thus further potentiating neurodegeneration Montojo et al. 2010). This would be consistent
(Zhang et al. 2005; Klegeris et al. 2008; Lee with the findings of early enteric a-synuclein
et al. 2010). It should be noted, however, that pathology in PD (Braak et al. 2006) and in a-
such studies are often based on high concentra- synuclein transgenic mice (Kuo et al. 2010). A
tions of recombinant a-synuclein that may not note of caution is indicated in the general as-
be physiologic. This issue is also touched on by sumption that seeding is equated with neuro-
Gendelman and colleagues (Mosley et al. in toxicity. In fact, seeding and toxicity of extracel-
press). lular a-synuclein can be dissociated (Danzer
A related aspect of a-synuclein pathobiol- et al. 2007).
ogy that has attracted a lot of attention is its ap-
parent ability to be uptaken by cells, although,
a-SYNUCLEIN BIOMARKERS
at least in cell culture, this is highly dependent
on the cell type and the particular species of In view of the importance of a-synuclein in
a-synuclein and is not easily achieved in intact PD pathogenesis, a number of studies have at-
neuronal cells (Emmanouilidou et al. 2010b). tempted to use measurements of a-synuclein
Oligomeric-aggregated a-synuclein species ap- as biomarkers for the disease and for other
pear to be especially prone to uptake and have synucleinopathies. In the cerebrospinal fluid
the potential to “seed” fibrillization of endoge- (CSF), most studies appear to show a reduction
nous a-synuclein (Danzer et al. 2007, 2009, of total a-synuclein levels in PD patients com-
2011; Luk et al. 2009; Nonaka et al. 2010; Wax- pared with controls (Tokuda et al. 2006; Mol-
man and Giasson 2010; Hansen et al. 2011). lenhauer et al. 2008, 2011; Hong et al. 2010; Ka-
This observation has created a lot of excitement, suga et al. 2010); in fact, a comprehensive study
as it could potentially explain the propagation suggested that a-synuclein levels, measured by a
of pathology observed in PD, according to the sensitive ELISA technique, may help to differen-
Braak hypothesis of staging of the disease. Two tiate synucleinopathies, where a-synuclein is
key in vivo observations support this “prionlike reduced compared with other neurodegenera-
propagation” theory. On the one hand, progen- tive conditions, such as tauopathies or amy-
itor cells implanted in the hippocampus of re- loidoses (Mollenhauer et al. 2011). In contrast,
cipient mice transgenic for a-synuclein incor- oligomeric a-synuclein, measured by a specific
porated host a-synuclein in their cell soma ELISA method, was higher in PD compared

L. Stefanis
Preventing
specific aberrant
functions
Synaptic
Enhancing
Modulating vesicles
degradation
transcription Proteasomes
Lysosomes
ER-Golgi
Cell membrane/Calcium
Mitochondria
Axonal transport
Inhibiting Promoting fibril

proaggregation Inhibiting
oligomer/protofibril formation
posttranslational
modifications formation
Promoting off-pathway
oligomers
Figure 2. Possible targets for therapeutic intervention in PD and related synucleinopathies.
with control CSF (Tokuda et al. 2010), extend- ACKNOWLEDGMENTS

ing previous findings of identification of soluble
L.S. was funded for PD-related research by EC
oligomeric a-synuclein in DLB brain tissue

FP7 Programmes NEURASYNC and MEFOPA.
(Paleologou et al. 2009), but this intriguing re-
sult awaits replication in a larger cohort. Data
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α-Synuclein in Parkinson's Disease

Leonidas Stefanis
Cold Spring Harb Perspect Med 2012; doi: 10.1101/cshperspect.a009399 originally published online
December 13, 2011
Subject Collection Parkinson's Disease
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Dawson Mark R. Cookson
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For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/
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a-Synuclein in Parkinson’s Disease

a-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropatholog-

Editor: Serge Przedborski

GENETICS OF PD AND OTHER tive risk for sporadic PD in initial association

the SNCA locus in separate families with an au-

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a-Synuclein in Parkinson’s Disease

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Repeat 1 Repeat 2 Repeat 3 Repeat 4 Repeat 5 Repeat 6

NAC region necessary for aggregation

Figure 1. Schemtic structure of a-synuclein.

mediated neurodegeneration (Hashimoto et al. modulated in conditions that alter plasticity or

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a-Synuclein in Parkinson’s Disease

show synaptic degeneration (Chandra et al. THE AGGREGATION POTENTIAL OF

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gesting that the preferential vulnerability of

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a-Synuclein in Parkinson’s Disease

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8 Cite this article as Cold Spring Harb Perspect Med 2012;4:a009399

a-Synuclein in Parkinson’s Disease

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10 Cite this article as Cold Spring Harb Perspect Med 2012;4:a009399

a-Synuclein in Parkinson’s Disease

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12 Cite this article as Cold Spring Harb Perspect Med 2012;4:a009399

a-Synuclein in Parkinson’s Disease

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Inhibiting Promoting fibril

Figure 2. Possible targets for therapeutic intervention in PD and related synucleinopathies.

with control CSF (Tokuda et al. 2010), extend- ACKNOWLEDGMENTS

oligomeric a-synuclein in DLB brain tissue

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a-Synuclein in Parkinson’s Disease

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Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis

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a-Synuclein in Parkinson’s Disease

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a-Synuclein in Parkinson’s Disease

induced by Parkinson’s-disease-related mutant a-synu- Martı̀n-Clemente B, Alvarez-Castelao B, Mayo I, Sierra AB,

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a-Synuclein in Parkinson’s Disease

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a-Synuclein in Parkinson’s Disease

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α-Synuclein in Parkinson's Disease

Subject Collection Parkinson's Disease

Functional Neuroanatomy of the Basal Ganglia Drosophila as a Model to Study Mitochondrial

For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/

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Stefanis - 2012 - α-Synuclein in Parkinson's Disease-annotated

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