The role of α-synuclein in Parkinson's disease: insights from animal models (original) (raw)
Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science276, 2045–2047 (1997). The first report showing that a missense mutation in the α-synuclein gene (A53T) causes an early-onset, familial form of PD. This was the first study to identify a genetic cause of PD. ArticleCASPubMed Google Scholar
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature392, 605–608 (1998). ArticleCASPubMed Google Scholar
Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science299, 256–259 (2003). ArticleCASPubMed Google Scholar
Mouradian, M. M. Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology58, 179–185 (2002). ArticlePubMed Google Scholar
Shimura, H. et al. Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science293, 263–269 (2001). ArticleCASPubMed Google Scholar
Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z. & Lansbury, P. T. Jr. The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility. Cell111, 209–218 (2002). ArticleCASPubMed Google Scholar
Miller, D. W. et al. L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin–proteasome system. J. Biol. Chem. 2003 Jul 8 (DOI: 10.1074/jbc.M304272200).
Mitsumoto, A. & Nakagawa, Y. DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Radic. Res.35, 885–893 (2001). ArticleCASPubMed Google Scholar
Mitsumoto, A. et al. Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat. Free Radic. Res.35, 301–310 (2001). ArticleCASPubMed Google Scholar
Wilson, M. A., Collins, J. L., Hod, Y., Ringe, D. & Petsko, G. A. The 1.1-Å resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. Proc. Natl Acad. Sci. USA100, 9256–9261 (2003). ArticleCASPubMedPubMed Central Google Scholar
Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature388, 839–840 (1997). The first study to demonstrate the presence of α-synuclein in the Lewy bodies and Lewy neurites of patients with idiopathic PD and Lewy body dementia. ArticleCASPubMed Google Scholar
Wakabayashi, K. et al. Synphilin-1 is present in Lewy bodies in Parkinson's disease. Ann. Neurol.47, 521–523 (2000). ArticleCASPubMed Google Scholar
Schlossmacher, M. G. et al. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am. J. Pathol.160, 1655–1667 (2002). ArticleCASPubMedPubMed Central Google Scholar
Kawamoto, Y. et al. 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains. J. Neuropathol. Exp. Neurol.61, 245–253 (2002). ArticleCASPubMed Google Scholar
Yamazaki, M. et al. α-Synuclein inclusions in amygdala in the brains of patients with the parkinsonism–dementia complex of Guam. J. Neuropathol. Exp. Neurol.59, 585–591 (2000). ArticleCASPubMed Google Scholar
Baba, M. et al. Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am. J. Pathol.152, 879–884 (1998). CASPubMedPubMed Central Google Scholar
Gai, W. P. et al. α-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy. Exp. Neurol.181, 68–78 (2003). ArticleCASPubMed Google Scholar
Conway, K. A., Harper, J. D. & Lansbury, P. T. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nature Med.4, 1318–1320 (1998). This work described the formation of α-synuclein protofibrils and fibrils during the process of fibrillization. A53T α-synuclein mutant protein was shown to fibrillize faster than wild-type protein. ArticleCASPubMed Google Scholar
Wood, S. J. et al. α-Synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. J. Biol. Chem.274, 19509–19512 (1999). ArticleCASPubMed Google Scholar
El-Agnaf, O. M. et al. Aggregates from mutant and wild-type α-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β-sheet and amyloid-like filaments. FEBS Lett.440, 71–75 (1998). ArticleCASPubMed Google Scholar
Giasson, B. I. & Lee, V. M. Parkin and the molecular pathways of Parkinson's disease. Neuron31, 885–888 (2001). ArticleCASPubMed Google Scholar
Conway, K. A. et al. Accelerated oligomerization by Parkinson's disease linked α-synuclein mutants. Ann. NY Acad. Sci.920, 42–45 (2000). ArticleCASPubMed Google Scholar
Conway, K. A. et al. Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc. Natl Acad. Sci. USA97, 571–576 (2000). This seminal study indicated that both α-synuclein mutations responsible for familial PD increase the rate of protofibril formation during the process of fibrillization. ArticleCASPubMedPubMed Central Google Scholar
Volles, M. J. & Lansbury, P. T. Jr. Vesicle permeabilization by protofibrillar α-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry41, 4595–4602 (2002). This paper demonstrated that α-synuclein protofibrils can permeabilize vesiclesin vitro, leading to the release of small cytoplasmic molecules such as DA. ArticleCASPubMed Google Scholar
Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature418, 291 (2002). ArticleCASPubMed Google Scholar
Xu, J. et al. Dopamine-dependent neurotoxicity of α-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nature Med.8, 600–606 (2002). ArticleCASPubMed Google Scholar
Lo Bianco, C., Ridet, J. L., Schneider, B. L., Deglon, N. & Aebischer, P. α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc. Natl Acad. Sci. USA99, 10813–10818 (2002). ArticleCASPubMedPubMed Central Google Scholar
Ostrerova-Golts, N. et al. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci.20, 6048–6054 (2000). ArticleCASPubMedPubMed Central Google Scholar
Kim, K. S. et al. The ceruloplasmin and hydrogen peroxide system induces α-synuclein aggregation in vitro. Biochimie84, 625–631 (2002). ArticleCASPubMed Google Scholar
Junn, E. & Mouradian, M. M. Human α-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci. Lett.320, 146–150 (2002). ArticleCASPubMed Google Scholar
Tabner, B. J., Turnbull, S., El-Agnaf, O. M. & Allsop, D. Formation of hydrogen peroxide and hydroxyl radicals from A(β) and α-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Free Radic. Biol. Med.32, 1076–1083 (2002). ArticleCASPubMed Google Scholar
George, J. M., Jin, H., Woods, W. S. & Clayton, D. F. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron15, 361–372 (1995). ArticleCASPubMed Google Scholar
Quilty, M. C., Gai, W. P., Pountney, D. L., West, A. K. & Vickers, J. C. Localization of α-, β-, and γ-synuclein during neuronal development and alterations associated with the neuronal response to axonal trauma. Exp. Neurol.182, 195–207 (2003). ArticleCASPubMed Google Scholar
Abeliovich, A. et al. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron25, 239–252 (2000). The first study to create α-synuclein-knockout mice, showing that α-synuclein deletion only led to slight changes in synaptic transmission. ArticleCASPubMed Google Scholar
Cabin, D. E. et al. Synaptic vesicle depletion with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein. J. Neurosci.22, 8797–8807 (2002). ArticleCASPubMedPubMed Central Google Scholar
Dauer, W. et al. Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc. Natl Acad. Sci. USA99, 14524–14529 (2002). These authors were the first to show that α-synuclein- knockout mice, and neuronal cultures derived from these mice, are resistant to the neurotoxin MPTP. ArticleCASPubMedPubMed Central Google Scholar
Schluter, O. M. et al. Role of α-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience118, 985–1002 (2003). ArticleCASPubMed Google Scholar
Fearnley, J. M. & Lees, A. J. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain114, 2283–2301 (1991). ArticlePubMed Google Scholar
Marsden, C. D. Problems with long-term levodopa therapy for Parkinson's disease. Clin. Neuropharmacol.17, S32–S44 (1994). ArticlePubMed Google Scholar
Dawson, T. M. & Dawson, V. L. Neuroprotective and neurorestorative strategies for Parkinson's disease. Nature Neurosci.5, S1058–S1061 (2002). ArticleCAS Google Scholar
Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science219, 979–980 (1983). ArticleCASPubMed Google Scholar
Cardellach, F. et al. Mitochondrial respiratory chain activity in skeletal muscle from patients with Parkinson's disease. Neurology43, 2258–2262 (1993). ArticleCASPubMed Google Scholar
Blin, O. et al. Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy. J. Neurol. Sci.125, 95–101 (1994). ArticleCASPubMed Google Scholar
Owen, A. D., Schapira, A. H., Jenner, P. & Marsden, C. D. Indices of oxidative stress in Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies. J. Neural Transm. Suppl.51, 167–173 (1997). ArticleCASPubMed Google Scholar
Liu, Y., Fiskum, G. & Schubert, D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J. Neurochem.80, 780–787 (2002). ArticleCASPubMed Google Scholar
Kang, J. H. & Kim, K. S. Enhanced oligomerization of the α-synuclein mutant by the Cu,Zn-superoxide dismutase and hydrogen peroxide system. Mol. Cells15, 87–93 (2003). CASPubMed Google Scholar
Forno, L. S., DeLanney, L. E., Irwin, I. & Langston, J. W. Electron microscopy of Lewy bodies in the amygdala–parahippocampal region. Comparison with inclusion bodies in the MPTP-treated squirrel monkey. Adv. Neurol.69, 217–228 (1996). CASPubMed Google Scholar
Spillantini, M. G. et al. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci. Lett.251, 205–208 (1998). ArticleCASPubMed Google Scholar
Kowall, N. W. et al. MPTP induces α-synuclein aggregation in the substantia nigra of baboons. Neuroreport11, 211–213 (2000). ArticleCASPubMed Google Scholar
Vila, M., Wu, D. C. & Przedborski, S. Engineered modeling and the secrets of Parkinson's disease. Trends Neurosci.24, S49–S55 (2001). ArticleCASPubMed Google Scholar
Kuhn, K. et al. The mouse MPTP model: gene expression changes in dopaminergic neurons. Eur. J. Neurosci.17, 1–12 (2003). ArticlePubMed Google Scholar
Beal, M. F. Experimental models of Parkinson's disease. Nature Rev. Neurosci.2, 325–334 (2001). ArticleCAS Google Scholar
Meredith, G. E. et al. Lysosomal malfunction accompanies α-synuclein aggregation in a progressive mouse model of Parkinson's disease. Brain Res.956, 156–165 (2002). ArticleCASPubMed Google Scholar
Neystat, M. et al. α-Synuclein expression in substantia nigra and cortex in Parkinson's disease. Mov. Disord.14, 417–422 (1999). ArticleCASPubMed Google Scholar
Gorell, J. M., Johnson, C. C., Rybicki, B. A., Peterson, E. L. & Richardson, R. J. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology50, 1346–1350 (1998). ArticleCASPubMed Google Scholar
Menegon, A., Board, P. G., Blackburn, A. C., Mellick, G. D. & Le Couteur, D. G. Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet352, 1344–1346 (1998). ArticleCASPubMed Google Scholar
Hensley, K. et al. Interaction of α-phenyl-N-tert-butyl nitrone and alternative electron acceptors with complex I indicates a substrate reduction site upstream from the rotenone binding site. J. Neurochem.71, 2549–2557 (1998). ArticleCASPubMed Google Scholar
Seaton, T. A., Cooper, J. M. & Schapira, A. H. Free radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors. Brain Res.777, 110–118 (1997). ArticleCASPubMed Google Scholar
Betarbet, R., Sherer, T. B. & Greenamyre, J. T. Animal models of Parkinson's disease. Bioessays24, 308–318 (2002). ArticleCASPubMed Google Scholar
Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci.3, 1301–1306 (2000). This study described the rotenone rat model of PD. These animals showed nigrostriatal system degeneration, Lewy-like inclusion bodies and motor impairment. ArticleCASPubMed Google Scholar
Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science287, 1265–1269 (2000). These authors were the first to develop α-synuclein transgenic mice. These mice were created using the PDGFβ promoter, and exhibited a loss of striatal dopaminergic terminals. ArticleCASPubMed Google Scholar
Auluck, P. K. & Bonini, N. M. Pharmacological prevention of Parkinson disease in Drosophila. Nature Med.8, 1185–1186 (2002). ArticleCASPubMed Google Scholar
Feany, M. B. & Bender, W. W. A Drosophila model of Parkinson's disease. Nature404, 394–398 (2000). The first published example of α-synucleinDrosophilatransgenics. The wild-type and mutant (A53T and A30P) α-synuclein transgenic flies exhibited DA neuron loss and neuronal inclusions resembling Lewy bodies. ArticleCASPubMed Google Scholar
Takahashi, M. et al. Phosphorylation of α-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Drosophila. Neurosci. Lett.336, 155–158 (2003). ArticleCASPubMed Google Scholar
Pendleton, R. G., Parvez, F., Sayed, M. & Hillman, R. Effects of pharmacological agents upon a transgenic model of Parkinson's disease in Drosophila melanogaster. J. Pharmacol. Exp. Ther.300, 91–96 (2002). ArticleCASPubMed Google Scholar
Fujiwara, H. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biol.4, 160–164 (2002). ArticleCASPubMed Google Scholar
Kahle, P. J. et al. Selective insolubility of α-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am. J. Pathol.159, 2215–2225 (2001). ArticleCASPubMedPubMed Central Google Scholar
Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet.23, 425–428 (1999). ArticleCASPubMed Google Scholar
Bonini, N. M. Chaperoning brain degeneration. Proc. Natl Acad. Sci. USA99, S16407–S16411 (2002). ArticleCAS Google Scholar
Yang, Y., Nishimura, I., Imai, Y., Takahashi, R. & Lu, B. Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron37, 911–924 (2003). ArticleCASPubMed Google Scholar
Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA100, 4078–4083 (2003). The first deletion of the parkin gene inDrosophila. The parkin-null flies exhibited muscle degeneration but no defects in the dopaminergic system. ArticleCASPubMedPubMed Central Google Scholar
Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science287, 2185–2195 (2000). ArticlePubMed Google Scholar
Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA94, 13287–13292 (1997). ArticleCASPubMedPubMed Central Google Scholar
Wiessner, C. et al. Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci. Lett.268, 119–122 (1999). ArticleCASPubMed Google Scholar
Kahle, P. J., Neumann, M., Ozmen, L. & Haass, C. Physiology and pathophysiology of α-synuclein. Cell culture and transgenic animal models based on a Parkinson's disease-associated protein. Ann. NY Acad. Sci.920, 33–41 (2000). ArticleCASPubMed Google Scholar
Matsuoka, Y. et al. Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol. Dis.8, 535–539 (2001). ArticleCASPubMed Google Scholar
Rathke-Hartlieb, S. et al. Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant α-synuclein transgenic mice. J. Neurochem.77, 1181–1184 (2001). ArticleCASPubMed Google Scholar
Richfield, E. K. et al. Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp. Neurol.175, 35–48 (2002). ArticleCASPubMed Google Scholar
Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron34, 521–533 (2002). ArticleCASPubMed Google Scholar
Lee, M. K. et al. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl Acad. Sci. USA99, 8968–8973 (2002). ArticleCASPubMedPubMed Central Google Scholar
Hashimoto, M., Rockenstein, E., Mante, M., Mallory, M. & Masliah, E. β-Synuclein inhibits α-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron32, 213–223 (2001). ArticleCASPubMed Google Scholar
Park, J. Y. & Lansbury, P. T. Jr. β-Synuclein inhibits formation of α-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease. Biochemistry42, 3696–3700 (2003). ArticleCASPubMed Google Scholar
Klein, R. L., King, M. A., Hamby, M. E. & Meyer, E. M. Dopaminergic cell loss induced by human A30P α-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther.13, 605–612 (2002). ArticleCASPubMed Google Scholar
Kirik, D. et al. Parkinson-like neurodegeneration induced by targeted overexpression of α-synuclein in the nigrostriatal system. J. Neurosci.22, 2780–2791 (2002). ArticleCASPubMedPubMed Central Google Scholar
Rochet, J. C., Conway, K. A. & Lansbury, P. T. Jr. Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse α-synuclein. Biochemistry39, 10619–10626 (2000). ArticleCASPubMed Google Scholar
Kirik, D. et al. Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson's disease. Proc. Natl Acad. Sci. USA100, 2884–2889 (2003). The first study attempting to create a primate model overexpressing the α-synuclein gene. These primates exhibited nigrostriatal degeneration, but lacked a motor phenotype resembling PD. ArticleCASPubMedPubMed Central Google Scholar
Uversky, V. N. & Fink, A. L. Amino acid determinants of α-synuclein aggregation: putting together pieces of the puzzle. FEBS Lett.522, 9–13 (2002). ArticleCASPubMed Google Scholar
Couzin, J. Parkinson's disease. Dopamine may sustain toxic protein. Science294, 1257–1258 (2001). ArticleCASPubMed Google Scholar
Hishikawa, N., Hashizume, Y., Yoshida, M. & Sobue, G. Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol. (Berl.)105, 341–350 (2003). Google Scholar
Conway, K. A., Rochet, J. C., Bieganski, R. M. & Lansbury, P. T. Jr. Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct. Science294, 1346–1349 (2001). This prominent work showed that DA stabilizes the protofibrillary conformation of α-synuclein. ArticleCASPubMed Google Scholar