Neuron 52, 33–38, October 5, 2006 ª2006 Elsevier Inc.DOI 10.1016/j.neuron.2006.09.026
ReviewMechanisms of Parkinson’s
Disease Linked to Pathological
a-Synuclein: New Targets for Drug Discovery
Virginia M.-Y. Lee1,* and John Q. Trojanowski1
1Department of Pathology and Laboratory Medicine
Center for Neurodegenerative Disease Research
Institute on Aging
Maloney Building, Third Floor
36thand Spruce Streets
University of Pennsylvania
Philadelphia, Pennsylvania 19104
Classic Parkinson’s disease (PD) is characterized by
fibrillar a-synuclein inclusions known as Lewy bodies
in the substantia nigra, which are associated with ni-
grostriatal degeneration. However, a-synuclein pa-
thologies accumulate throughout the CNS in areas
that also undergo progressive neurodegeneration,
leading to dementia and other behavioral impairments
in addition to parkinsonism. Although mutations in
the a-synuclein gene only cause Lewy body PD in
rare families, and although there are multiple other,
albeit rare, genetic causes of familial parkinsonism,
sporadic Lewy body PD is the most common
movement disorder, and insights into mechanisms
underlying a-synuclein-mediated neurodegeneration
provide novel targets for the discovery of disease-
modifying therapies for PD and related neurodegener-
Long before the description of Parkinson’s disease (PD)
by James Parkinson nearly 200 years ago, there were
accounts of a clinical syndrome consisting of tremor
and akinesia described in Indian medical (Ayurvedic)
texts written >3000 years ago (Manyam, 1990; Kat-
zenschlager et al., 2004). Remarkably, this syndrome,
termed kampavata in Sanskrit, was treated with natural
products from Mucuna pruriens, a plant now known to
contain levodopa (L-dopa), the symptomatic drug inter-
vention that revolutionized PD therapy in the mid-20th
Century. However, our understanding of mechanisms
underlying the onset and progression of PD is undergo-
ing a second, more profound revolution initiated by the
identification of mutations in the gene encoding a-synu-
clein (SNCA) and the demonstration that a-synuclein is
the principal component of filamentous Lewy bodies
(Polymeropoulos et al., 1997; Spillantini et al., 1997).
Indeed, these and subsequent insights into the normal
biology and function of a-synuclein and the role of a-
synuclein pathologies in PD are reorienting the design
of drug discovery efforts to focus on targets related to
a-synuclein misfolding and fibrillization into filamentous
Lewy bodies and Lewy neurites, as well as other poten-
tial pathogenic pathways involving a-synuclein oxida-
tion/nitration and degradation (Cookson, 2005; Feany,
2004; Forman et al., 2005; Giasson et al., 2004b; Savitt
uclein-mediated neurodegenerative mechanisms to PD
will have a powerful impact on the development of dis-
ease-modifying therapies for PD and related disorders
characterized by a-synuclein pathologies. Here we re-
view recent advances in understanding the role of path-
ologically altered forms of a-synuclein in the onset and
progression of PD, as well as the implications thereof
for developing novel disease-modifying therapies for
PD and related neurodegenerative disorders that are
characterized neuropathologically by abundant accu-
mulations of a-synuclein inclusions throughout the
central nervous system (CNS). (Note that due to the ex-
plosive growth in new information on the genetic and
molecular pathology of PD, only limited recent primary
publications are listed, and earlier literature is available
in reviews cited here.)
a-Synuclein and Lewy Body Parkinson’s Disease
The most common neurodegenerative movement disor-
sively with advancing age such that it affects about 1%
ofindividuals who are65 yearsofage,but 5% ormoreof
those individuals 85 years of age and older. Lewy body
PD is characterized clinically by L-dopa-responsive mo-
tor impairments that include (1) bradykinesia, (2) in-
creased muscle tone, (3) resting tremor, and (4) abnor-
mal postural righting reflexes, although it is well known
that the clinical phenotype of Lewy body PD overlaps
with other new and previously described forms of par-
kinsonism (Forman et al., 2005; Giasson et al., 2004b;
Savitt et al., 2006). Although there was considerable
skepticism about the existence of a genetic etiology of
PD throughout the 20thCentury, these doubts were dis-
pelled following the report of the first pathogenic SNCA
mutation in familial PD in 1997. Since then, over a dozen
additional genes and genetic loci have been implicated
as causes of Lewy body PD or other familial Parkinson
syndromes. Thus, as reviewed elsewhere (Feany, 2004;
Forman et al., 2005; Giasson et al., 2004b; Savitt et al.,
2006), there are multiple, seemingly unrelated genetic
causes of nigrostriatal degeneration that manifest as
parkinsonism, with and without Lewy bodies. And, while
familial PD caused by a-synuclein mutations is ex-
tremely rare, PD characterized by a-synuclein contain-
ing Lewy bodies accounts for >90% of sporadic Parkin-
sonian disorders (Feany, 2004; Forman et al., 2005;
Savitt et al., 2006).
Normal a-Synuclein and Its Putative Function
a-Synuclein is an abundant, 140 amino acid long, highly
soluble neuronal cytoplasmic protein that is, for the
most part, unstructured in aqueous solution. It is pre-
dominantly localized to presynaptic terminals in the
CNS, where it is loosely associated with synaptic vesi-
cles (Cookson, 2005; Giasson et al., 2004b; Savitt
et al., 2006). While the exact functions of normal a-syn-
uclein remain to be fully elucidated, studies in songbirds
suggest it may play a role in synaptic plasticity, and data
obtained from studies of a-synuclein knockout mice,
though controversial, indicate that this synaptic pro-
tein may be involved in activity-dependent negative
platform in cerebrospinal fluid of patients with neurodegenerative
disorders. J. Alzheimers Dis. 9, 293–348.
Bilen, J., and Bonini, N.M. (2005). Drosophila as a model for human
neurodegenerative disease. Annu. Rev. Genet. 39, 153–171.
Chandra, S., Gallardo, G., Fernadez-Chacon, R., Schluter, O.M., and
Sudhof, T.C. (2005). Alpha-synuclein cooperates with CSPalpha in
preventing neurodegeneration. Cell 123, 383–396.
Chartier-Harlin, M.C., Kachergus, J., Roumier, C., Mouroux, V.,
M., et al. (2004). Alpha-synuclein locus duplication as a cause of
familial Parkinson’s disease. Lancet 364, 1167–1169.
Conway, K.A., Rochet, J.C., Bieganski, R.M., and Lansbury, P.T., Jr.
(2001). Kinetic stabilization of the alpha-synuclein protofibril by a
dopamine-alpha-synuclein adduct. Science 294, 1346–1349.
Cookson, M.R. (2005). The biochemistry of Parkinson’s disease.
Annu. Rev. Biochem. 74, 29–52.
Cooper,A.A., Gitler,A.D., Cashikar, A.,Haynes, C.M.,Hill, K.J.,Bhul-
lar, B., Liu, K., Xu, K., Strathearn, K.E., Liu, F., et al. (2006). Alpha-
synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in
Parkinson’s models. Science 313, 324–328.
Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T., and
Sulzer, D. (2004). Impaired degradation of mutant alpha-synuclein
by chaperone-mediated autophagy. Science 305, 1292–1295.
Fan, Y., Limprasert, P., Murray, I.V.J., Smith, A.C., Lee, V.M.-Y.,
Trojanowski, J.Q., Sopher, B.L., and La Spada, A.R. (2006). Beta-
synuclein modulates alpha-synuclein neurotoxicity by reducing
alpha-synuclein protein expression. Hum. Mol. Genet., in press.
Feany, M.B. (2004). New genetic insights into Parkinson’s disease.
N. Engl. J. Med. 351, 1937–1940.
Forman, M.S., Lee, V.M.-Y., and Trojanowski, J.Q. (2005). Nosology
of Parkinson’s disease: Looking for the way out of a quagmire. Neu-
ron 47, 479–482.
Giasson, B.I., Lee, V.M.-Y., and Trojanowski, J.Q. (2004a). Animal
models of neurodegenerative dementing disorders other than Alz-
heimer’s disease. Clin. Neurosci. Res. 3, 427–436.
Giasson, B.I., Lee, V.M.-Y., and Trojanowski, J.Q. (2004b). Parkin-
son’s disease, dementia with Lewy bodies, multiple system atrophy
and the spectrum of diseases with alpha-synuclein inclusions. In
The Neuropathology Of Dementia, M. Esiri, V.M.-Y. Lee, and J.Q.
Trojanowski, eds. (Cambridge: Cambridge University Press),
Greenamyre, J.T., and Hastings, T.G. (2004). Parkinson’s–divergent
causes, convergent mechanisms. Science 304, 1120–1122.
Hashimoto, M., Rockentein, E., Mante, M., Mallory, M., and Masliah,
E. (2001). Beta-Synuclein inhibits alpha-synuclein aggregation:
a possible role as an anti-parkinsonian factor. Neuron 32, 213–223.
Katzenschlager, R., Evans, A., Manson, A., Patsalos, P.N., Ratnaraj,
N., Watt, H., Timmermann, L., Van der Giessen, R., and Lees, A.J.
(2004). Mucuna pruriens in Parkinson’s disease: a double blind clin-
Kotzbauer, P.T., Giasson, B.I., Kravitz, A.V., Golbe, L.I., Mark, M.H.,
Trojanowski, J.Q., and Lee, V.M.-Y. (2004). Fibrillization of alpha-
synuclein and tau in familial Parkinson’s disease caused by the
A53T alpha-synuclein mutation. Exp. Neurol. 187, 279–288.
Manyam, B.V. (1990). Paralysis agitans and levodopa in ‘‘Ayurveda’’:
ancient Indian medical treatise. Mov. Disord. 5, 47–48.
McKeith, I.G., Dickson, D.W., Lowe, J., Emre, M., O’Brien, J.T., Feld-
man, H., Cummings, J., Duda, J., Lippa, and , et al.for the Consor-
tium on DLB. (2005). Dementia with Lewy Bodies: Diagnosis and
Management: Third Report of the DLB Consortium. Neurology 65,
Norris, E.H., Giasson, B.I., Hodara, R., Xu, S., Trojanowski, J.Q.,
Ischiropoulos, H., and Lee, V.M.-Y. (2005). Reversible inhibition of
alpha-synuclein fibrillization by dopaminochrome mediated confor-
mational alterations. J. Biol. Chem. 280, 21212–21219.
Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A.,
Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997).
Mutation in the alpha-synuclein gene identified in families with Par-
kinson’s disease. Science 276, 2045–2047.
Rochet, J.C., Outeiro, T.F., Conway, K.A., Ding, T.T., Volles, M.J.,
Lashuel, H.A., Bieganski, R.M., Lindquist, S.L., and Lansbury, P.T.
(2004). Interactions among alpha-synuclein, dopamine, and bio-
membranes: some clues for understanding neurodegeneration in
Parkinson’s disease. J. Mol. Neurosci. 23, 23–34.
Ronald & Nancy Reagan Institute of the Alzheimer’s Association &
National Institute on Aging Working Group on Biological Markers
of Alzheimer’s Disease Disease (1998). Consensus report of the
Working Group on Biological Markers of Alzheimer’s Disease. Neu-
robiol. Aging 19, 109–116.
Savitt, J.M., Dawson, V.L., and Dawson, T.M. (2006). Diagnosis and
treatment of Parkinson disease: Molecules to medicine. J. Clin.
Invest. 116, 1744–1754.
Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S.,
Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum,
R., et al. (2003). alpha-Synuclein locus triplication causes Parkin-
son’s disease. Science 302, 841.
Skovronsky, D.M., Lee, V.M.-Y., and Trojanowski, J.Q. (2006). Neu-
rodegenerative diseases: New concepts of pathogenesis and their
therapeutic implications. Annu. Rev. Pathol. Mech. Dis. 1, 151–170.
Spillantini, M.G., Schmidt, M.L., Lee, V.M.-Y., Trojanowski, J.Q.,
Jakes, R., and Goedert, M. (1997). Alpha-synuclein in Lewy bodies.
Nature 388, 839–840.
Thal, L.J., Kantarci, K., Reiman, E.M., Klunk, W.E., Weiner, M.W.,
Zetterberg, H., Galasko, D., Pratico, D., Griffin, S., Schenk, D., and
Siemers, E. (2006). The role of biomarkers in clinical trials for
Alzheimer disease. Alzheimer Dis. Assoc. Disord. 20, 6–15.
Tofaris, G.K., Garcia Reitbock, P., Humby, T., Lambourne, S.L.,
O’Connell, M., Ghetti, B., Gossage, H., Emson, P.C., Wilkinson,
L.S., Goedert, M., and Spillantini, M.G. (2006). Pathological changes
in dopaminergic nerve cells of the substantia nigra and olfactory
bulb in mice transgenic for truncated human alpha-synuclein(1-
120): implications for Lewy body disorders. J. Neurosci. 26, 3942–
Tokuda, T., Salem, S.A., Allsop, D., Mizuno, T., Nakagawa, M., Qur-
eshi,M.M.,Locascio,J.J., Schlossmacher, M.G., andEl-Agnaf, O.M.
(2006). Decreased alpha-synuclein in cerebrospinal fluid of aged in-
dividuals and subjects with Parkinson’s disease. Biochem. Biophys.
Res. Commun. 349, 162–166.
Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln,
S., Kachergus, J., Hulihan, M., Uitti, R.J., Calne, D.B., et al. (2004).
Mutations in LRRK2 cause autosomal-dominant parkinsonism with
pleomorphic pathology. Neuron 44, 601–607.