Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein (original) (raw)

• Kruger, R., Eberhardt, O., Riess, O., Schulz, J. B. & Riess, O. Parkinson's disease: one biochemical pathway to fit all genes? Trends Mol. Med. 8, 236–240 (2002).
  CAS PubMed Google Scholar
• Lansbury, P. T. & Brice, A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr. Opin. Genet. Dev. 12, 299–306 (2002).
  CAS PubMed Google Scholar
• Sherer, T. B., Betarbet, R. & Greenamyre, J. T. Pathogenesis of Parkinson's disease. Curr. Opin. Investig. Drugs 2, 657–662 (2001).
  CAS PubMed Google Scholar
• Duda, J. E., Giasson, B. I., Mabon, M. E., Lee, V. M. & Trojanowski, J. Q. Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann. Neurol. 52, 205–210 (2002).
  CAS PubMed Google Scholar
• Sauer, H. & Oertel, W. H. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59, 401–415 (1994).
  CAS PubMed Google Scholar
• Lee, C. S., Sauer, H. & Bjorklund, A. Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat. Neuroscience 72, 641–653 (1996).
• Sohal, R. S. & Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 273, 59–63 (1996).
  CAS PubMed PubMed Central Google Scholar
• Smith, C. D. et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc. Natl Acad. Sci. USA 88, 10540–10543 (1991).
  CAS PubMed PubMed Central Google Scholar
• Mecocci, P. et al. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann. Neurol. 34, 609–616 (1993).
  CAS PubMed Google Scholar
• Mecocci, P., MacGarvey, U. & Beal, M. F. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann. Neurol. 36, 747–751 (1994).
  CAS PubMed Google Scholar
• Lovell, M. A., Ehmann, W. D., Butler, S. M. & Markesbery, W. R. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease. Neurology 45, 1594–1601 (1995).
  CAS PubMed Google Scholar
• Marcus, D. L. et al. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. Exp. Neurol. 150, 40–44 (1998).
  CAS PubMed Google Scholar
• Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).
  CAS PubMed Google Scholar
• Ferrante, R. J. et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J. Neurochem. 69, 2064–2074 (1997).
  CAS PubMed Google Scholar
• Pedersen, W. A. et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann. Neurol. 44, 819–824 (1998).
  CAS PubMed Google Scholar
• Graham, D. G. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol. Pharmacol. 14, 633–643 (1978).
  CAS PubMed Google Scholar
• Maker, H. S., Weiss, C., Silides, D. J. & Cohen, G. Coupling of dopamine oxidation (monoamine oxidase activity) to glutathione oxidation via the generation of hydrogen peroxide in rat brain homogenates. J. Neurochem. 36, 589–593 (1981).
  CAS PubMed Google Scholar
• Halliwell, B. Reactive oxygen species and the central nervous system. J. Neurochem. 59, 1609–1623 (1992).
  CAS PubMed Google Scholar
• Jenner, P. Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov. Disord. 13 (Suppl. 1), 24–34 (1998).
  PubMed Google Scholar
• Sofic, E. et al. Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J. Neural Transm. 74, 199–205 (1988).
  CAS PubMed Google Scholar
• Saggu, H. et al. A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra. J. Neurochem. 53, 692–697 (1989).
  CAS PubMed Google Scholar
• Dexter, D. T. et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem. 52, 381–389 (1989).
  CAS PubMed Google Scholar
• Floor, E. & Wetzel, M. G. Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. J. Neurochem. 70, 268–275 (1998).
  CAS PubMed Google Scholar
• Alam, Z. I. et al. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J. Neurochem. 69, 1196–1203 (1997).
  CAS PubMed Google Scholar
• Dexter, D. T. et al. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J. Neurochem. 52, 1830–1836 (1989).
  CAS PubMed Google Scholar
• Yoritaka, A. et al. Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc. Natl Acad. Sci. USA 93, 2696–2701 (1996).
  CAS PubMed PubMed Central Google Scholar
• Zhang, J. et al. Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am. J. Pathol. 154, 1423–1429 (1999).
  CAS PubMed PubMed Central Google Scholar
• Alam, Z. I. et al. A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. J. Neurochem. 69, 1326–1329 (1997).
  CAS PubMed Google Scholar
• Schulz, J. B., Lindenau, J., Seyfried, J. & Dichgans, J. Glutathione, oxidative stress and neurodegeneration. Eur. J. Biochem. 267, 4904–4911 (2000).
  CAS PubMed Google Scholar
• Marttila, R. J., Lorentz, H. & Rinne, U. K. Oxygen toxicity protecting enzymes in Parkinson's disease. Increase of superoxide dismutase-like activity in the substantia nigra and basal nucleus. J. Neurol. Sci. 86, 321–331 (1988).
  CAS PubMed Google Scholar
• Ben-Shachar, D., Riederer, P. & Youdim, M. B. Iron–melanin interaction and lipid peroxidation: implications for Parkinson's disease. J. Neurochem. 57, 1609–1614 (1991).
  CAS PubMed Google Scholar
• Riederer, P. et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52, 515–520 (1989).
  CAS PubMed Google Scholar
• Jellinger, K. et al. Iron–melanin complex in substantia nigra of parkinsonian brains: an X-ray microanalysis. J. Neurochem. 59, 1168–1171 (1992).
  CAS PubMed Google Scholar
• Dexter, D. T. et al. Nigral dopaminergic cell loss in vitamin E deficient rats. Neuroreport 5, 1773–1776 (1994).
  CAS PubMed Google Scholar
• Przedborski, S. & Jackson-Lewis, V. Mechanisms of MPTP toxicity. Mov. Disord. 13 (Suppl. 1), 35–38 (1998).
  PubMed Google Scholar
• Del Zompo, M., Piccardi, M. P., Ruiu, S., Corsini, G. U. & Vaccari, A. High-affinity binding of [3H]1-methyl-4-phenyl-2,3-dihydropyridinium ion to mouse striatal membranes: putative vesicular location. Eur. J. Pharmacol. 202, 293–294 (1991).
  CAS PubMed Google Scholar
• Del Zompo, M., Piccardi, M. P., Ruiu, S., Corsini, G. U. & Vaccari, A. Characterization of a putatively vesicular binding site for [3H]MPP+ in mouse striatal membranes. Brain Res. 571, 354–357 (1992).
  CAS PubMed Google Scholar
• Peter, D., Jimenez, J., Liu, Y., Kim, J. & Edwards, R. H. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J. Biol. Chem. 269, 7231–7237 (1994).
  CAS PubMed Google Scholar
• Nicklas, W. J., Vyas, I. & Heikkila, R. E. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci. 36, 2503–2508 (1985).
  CAS PubMed Google Scholar
• Ramsay, R. R., Salach, J. I. & Singer, T. P. Uptake of the neurotoxin 1-methyl-4-phenylpyridine (MPP+) by mitochondria and its relation to the inhibition of the mitochondrial oxidation of NAD+-linked substrates by MPP+. Biochem. Biophys. Res. Commun. 134, 743–748 (1986).
  CAS PubMed Google Scholar
• Ramsay, R. R. et al. Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase. J. Neurochem. 56, 1184–1190 (1991).
  CAS PubMed Google Scholar
• Denton, T. & Howard, B. D. A dopaminergic cell line variant resistant to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Neurochem. 49, 622–630 (1987).
  CAS PubMed Google Scholar
• Krueger, M. J., Singer, T. P., Casida, J. E. & Ramsay, R. R. Evidence that the blockade of mitochondrial respiration by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) involves binding at the same site as the respiratory inhibitor, rotenone. Biochem. Biophys. Res. Commun. 169, 123–128 (1990).
  CAS PubMed Google Scholar
• Lotharius, J. & O'Malley, K. L. The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity. J. Biol. Chem. 275, 38581–38588 (2000).The first study to show that dopamine-dependent oxidative stress contributes to the toxicity of the parkinsonism-inducing drug MPTP.
  CAS PubMed Google Scholar
• Jones, S. R., Gainetdinov, R. R., Wightman, R. M. & Caron, M. G. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J. Neurosci. 18, 1979–1986 (1998).
  CAS PubMed PubMed Central Google Scholar
• Sulzer, D. & Rayport, S. Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action. Neuron 5, 797–808 (1990).The first study to show that amphetamine leads to the cytoplasmic accumulation of dopamine by disrupting the pH gradient across vesicular membranes, which provides the proton-motive force required by the vesicular monoamine transporter.
  CAS PubMed Google Scholar
• Sulzer, D. et al. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J. Neurosci. 15, 4102–4108 (1995).The first report to show that amphetamine promotes reverse transport of dopamine through the plasma-membrane dopamine transporter after its redistribution from vesicles to the cytosol.
  CAS PubMed PubMed Central Google Scholar
• Seiden, L. S., Commins, D. L., Vosmer, G., Axt, K. & Marek, G. Neurotoxicity in dopamine and 5-hydroxytryptamine terminal fields: a regional analysis in nigrostriatal and mesolimbic projections. Ann. NY Acad. Sci. 537, 161–172 (1988).
  CAS PubMed Google Scholar
• Sonsalla, P. K., Jochnowitz, N. D., Zeevalk, G. D., Oostveen, J. A. & Hall, E. D. Treatment of mice with methamphetamine produces cell loss in the substantia nigra. Brain Res. 738, 172–175 (1996).
  CAS PubMed Google Scholar
• Schmidt, C. J., Ritter, J. K., Sonsalla, P. K., Hanson, G. R. & Gibb, J. W. Role of dopamine in the neurotoxic effects of methamphetamine. J. Pharmacol. Exp. Ther. 233, 539–544 (1985).By showing that rats pretreated with a dopamine-synthesis inhibitor show less toxicity in response to methamphetamine than non-treated rats, this study was one of the first to suggest that dopamine is involved in the neurotoxic actions of this psychostimulant.
  CAS PubMed Google Scholar
• De Vito, M. J. & Wagner, G. C. Methamphetamine-induced neuronal damage: a possible role for free radicals. Neuropharmacology 28, 1145–1150 (1989).
  CAS PubMed Google Scholar
• Cadet, J. L., Ladenheim, B., Baum, I., Carlson, E. & Epstein, C. CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA). Brain Res. 655, 259–262 (1994).
  CAS PubMed Google Scholar
• Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci. 3, 1301–1306 (2000).
  CAS PubMed Google Scholar
• McCormack, A. L. et al. Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol. Dis. 10, 119–127 (2002).
  CAS PubMed Google Scholar
• Le Couteur, D. G., McLean, A. J., Taylor, M. C., Woodham, B. L. & Board, P. G. Pesticides and Parkinson's disease. Biomed. Pharmacother. 53, 122–130 (1999).
  CAS PubMed Google Scholar
• Liou, H. H. et al. Environmental risk factors and Parkinson's disease: a case-control study in Taiwan. Neurology 48, 1583–1588 (1997).
  CAS PubMed Google Scholar
• Fukushima, T., Yamada, K., Isobe, A., Shiwaku, K. & Yamane, Y. Mechanism of cytotoxicity of paraquat. I. NADH oxidation and paraquat radical formation via complex I. Exp. Toxicol. Pathol. 45, 345–349 (1993).
  CAS PubMed Google Scholar
• Lewy, F. in Handbuch der Neurologie Vol. 3 (eds Lewandowski, M. & Abelsdorff, G.) 920–933 (Springer, Berlin, 1912).
  Google Scholar
• Goedert, M. α-Synuclein and neurodegenerative diseases. Nature Rev. Neurosci. 2, 492–501 (2001).
  CAS Google Scholar
• Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).
  CAS PubMed Google Scholar
• George, J. M. The synucleins. Genome Biol. 3, reviews3002.1–3002.6 (2002). | PubMed |
  Google Scholar
• Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).The first study to link mutations in the α-synuclein gene to familial Parkinson's disease.
  CAS PubMed Google Scholar
• Krüger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nature Genet. 18, 106–108 (1998).
  PubMed Google Scholar
• Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
  CAS PubMed Google Scholar
• Giasson, B. I. & Lee, V. M. Parkin and the molecular pathways of Parkinson's disease. Neuron 31, 885–888 (2001).
  CAS PubMed Google Scholar
• Leroy, E. et al. The ubiquitin pathway in Parkinson's disease. Nature 395, 451–452 (1998).
  CAS PubMed 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. Cell 111, 209–218 (2002).
  CAS PubMed Google Scholar
• Kuzuhara, S., Mori, H., Izumiyama, N., Yoshimura, M. & Ihara, Y. Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. (Berl.) 75, 345–353 (1988).
  CAS Google Scholar
• Ii, K., Ito, H., Tanaka, K. & Hirano, A. Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J. Neuropathol. Exp. Neurol. 56, 125–131 (1997).
  CAS PubMed Google Scholar
• Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. & Bonini, N. M. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865–868 (2002).
  CAS PubMed Google Scholar
• Galvin, J. E. et al. Monoclonal antibodies to purified cortical Lewy bodies recognize the mid-size neurofilament subunit. Ann. Neurol. 42, 595–603 (1997).
  CAS PubMed Google Scholar
• Conway, K. A., Harper, J. D. & Lansbury, P. T. Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry 39, 2552–2563 (2000).
  CAS PubMed 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. USA 97, 571–576 (2000).The first study to show that both α-synuclein mutations increase the protein's ability to form oligomers, key intermediates in the aggregation process.
  CAS PubMed PubMed Central Google Scholar
• Bucciantini, M. et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511 (2002).The first paper to show that prefibrillar, aggregated forms of non-disease-associated proteins are highly toxic to cells.
  CAS PubMed Google Scholar
• Goldberg, M. S. & Lansbury, P. T. Jr. Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson's disease? Nature Cell Biol. 2, E115–E119 (2002).
  Google Scholar
• Lee, H. J. & Lee, S. J. Characterization of cytoplasmic α-synuclein aggregates: fibril formation is tightly linked to the inclusion forming process in cells. J. Biol. Chem. 25 September 2002 (doi:10.1074/jbc.M208192200). | PubMed |
• Gosavi, N., Lee, H. J., Lee, J. S., Patel, S. & Lee, S. J. Golgi fragmentation occurs in the cells with prefibrillar α-synuclein aggregates and precedes the formation of fibrillar inclusion. J. Biol. Chem. 25 September 2002 (doi:10.1074/jbc.M208194200).
• Tompkins, M. M. & Hill, W. D. Contribution of somal Lewy bodies to neuronal death. Brain Res. 775, 24–29 (1997).
  CAS PubMed Google Scholar
• Hurtig, H. I. et al. α-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology 54, 1916–1921 (2000).
  CAS PubMed Google Scholar
• Mattila, P. M., Rinne, J. O., Helenius, H., Dickson, D. W. & Roytta, M. α-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease. Acta Neuropathol. (Berl.) 100, 285–290 (2000).
  CAS Google Scholar
• Shtilerman, M. D., Ding, T. T. & Lansbury, P. T. Jr. Molecular crowding accelerates fibrillization of α-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease? Biochemistry 41, 3855–3860 (2002).
  CAS PubMed 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. Science 294, 1346–1349 (2001).
  CAS PubMed Google Scholar
• Volles, M. J. et al. Vesicle permeabilization by protofibrillar α-synuclein: implications for the pathogenesis and treatment of Parkinson's disease. Biochemistry 40, 7812–7819 (2001).This study shows that protofibrillar α-synuclein can permeabilize vesicles, allowing the leakage of small molecules, such as dopamine, which could potentially lead to an increase in cytoplasmic dopamine levels.
  CAS PubMed 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. Biochemistry 41, 4595–4602 (2002).
  CAS PubMed Google Scholar
• Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002).
  CAS PubMed Google Scholar
• Lashuel, H. et al. α-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 322, 1089 (2002).
  CAS PubMed Google Scholar
• Hashimoto, M. et al. Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro. Neuroreport 10, 717–721 (1999).
  CAS PubMed Google Scholar
• Kim, K. S. et al. Aggregation of α-synuclein induced by the Cu,Zn-superoxide dismutase and hydrogen peroxide system. Free Radic. Biol. Med. 32, 544–550 (2002).
  CAS PubMed Google Scholar
• Sherman, M. Y. & Goldberg, A. L. Involvement of molecular chaperones in intracellular protein breakdown. EXS 77, 57–78 (1996).
  CAS PubMed Google Scholar
• Zhang, Y. et al. Parkin functions as an E2-dependent ubiquitin–protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl Acad. Sci USA 97, 13354–13359 (2000).
  CAS PubMed PubMed Central Google Scholar
• Shimura, H. et al. Parkinson disease gene product, parkin, is a ubiquitin–protein ligase. Nature Genet. 25, 302–305 (2000).References 90 and 91 show that parkin is a key enzyme in the ubiquitin–proteasome system, and is essential for the degradation of cellular proteins.
  CAS PubMed Google Scholar
• West, A. B. et al. Functional association of the parkin gene promoter with idiopathic Parkinson's disease. Hum. Mol. Genet. 11, 2787–2792 (2002).
  CAS PubMed Google Scholar
• Farrer, M. et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann. Neurol. 50, 293–300 (2001).
  CAS PubMed Google Scholar
• Chung, K. K. et al. Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature Med. 7, 1144–1150 (2001).
  CAS PubMed Google Scholar
• Engelender, S. et al. Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions. Nature Genet. 22, 110–114 (1999).
  CAS PubMed Google Scholar
• Ribeiro, C. S., Carneiro, K., Ross, C. A., Menezes, J. R. & Engelender, S. Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by α-synuclein. J. Biol. Chem. 277, 23927–23933 (2002).
  CAS PubMed Google Scholar
• Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin–proteasome system by protein aggregation. Science 292, 1552–1555 (2001).
  CAS PubMed Google Scholar
• McNaught, K. St P. & Jenner, P. Proteasomal function is impaired in substantia nigra in Parkinson's disease. Neurosci. Lett. 297, 191–194 (2001).
  CAS PubMed Google Scholar
• Furukawa, Y. et al. Brain proteasomal function in sporadic Parkinson's disease and related disorders. Ann. Neurol. 51, 779–782 (2002).
  PubMed Google Scholar
• McNaught, K. S., Belizaire, R., Jenner, P., Olanow, C. W. & Isacson, O. Selective loss of 20S proteasome α-subunits in the substantia nigra pars compacta in Parkinson's disease Neurosci. Lett. 326, 155–158 (2002).
  CAS PubMed Google Scholar
• Rideout, H. J., Larsen, K. E., Sulzer, D. & Stefanis, L. Proteasomal inhibition leads to formation of ubiquitin/α-synuclein-immunoreactive inclusions in PC12 cells. J. Neurochem. 78, 899–908 (2001).
  CAS PubMed Google Scholar
• McNaught, K. S. et al. Proteasome inhibition causes nigral degeneration with inclusion bodies in rats. Neuroreport 13, 1437–1441 (2002).
  CAS PubMed Google Scholar
• McNaught, K. S. et al. Impairment of the ubiquitin–proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J. Neurochem. 81, 301–306 (2002).
  CAS PubMed Google Scholar
• Abeliovich, A. et al. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239–252 (2000).The first group to delete the α-synuclein gene in mice report subtle defects in synaptic transmission but not in overt phenotype.
  CAS PubMed Google Scholar
• Cabin, D. E. et al. Synaptic vesicle depletion in mice lacking α-synuclein. J. Neurosci. 22, 8797–8807 (2002).
  CAS PubMed PubMed Central Google Scholar
• Dauer, W. et al. Resistance of α-synuclein null mice to the parkinsonism-inducing neurotoxin MPTP. Proc. Natl Acad. Sci. USA 99, 14524–14529 (2002).
  CAS PubMed PubMed Central Google Scholar
• Lotharius, J. et al. Effect of mutant α-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J. Biol. Chem. 277, 38884–38894 (2002).This paper shows that mutant α-synuclein might increase cytoplasmic levels of dopamine in human mesencephalic cells.
  CAS PubMed Google Scholar
• Hansson, O. et al. Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. Proc. Natl Acad. Sci. USA 96, 8727–8732 (1999).
  CAS PubMed PubMed Central Google Scholar
• Hansson, O. et al. Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene. Eur. J. Neurosci. 14, 1492–1504 (2001).
  CAS PubMed Google Scholar
• Tyagi, P. & Tayal, G. Ischemic preconditioning of myocardium. Acta Pharmacol. Sin. 23, 865–870 (2002).
  CAS PubMed Google Scholar
• Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000).This was the first α-synuclein transgenic mouse to be created; it overexpresses human wild-type α-synuclein under the control of the platelet-derived growth factor-β promoter. This is the only paper so far to report a nigrostriatal defect in mice that overexpress any form of α-synuclein.
  CAS PubMed Google Scholar
• Putten, H. et al. Neuropathology in mice expressing human α-synuclein. J. Neurosci. 20, 6021–6029 (2000).
  PubMed PubMed Central Google Scholar
• Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521–533 (2002).
  CAS PubMed 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. USA 99, 8968–8973 (2002).
  CAS PubMed PubMed Central Google Scholar
• Feany, M. B. & Bender, W. W. A Drosophila model of Parkinson's disease. Nature 404, 394–398 (2000).
  CAS PubMed Google Scholar
• Stein, T. D. & Johnson, J. A. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J. Neurosci. 22, 7380–7388 (2002).
  CAS PubMed PubMed Central Google Scholar
• Zhou, W., Schaack, J., Zawada, W. M. & Freed, C. R. Overexpression of human α-synuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res. 926, 42–50 (2002).
  CAS PubMed Google Scholar
• Xu, J. et al. Dopamine-dependent neurotoxicity of α-synuclein: a mechanism for selective neurodegeneration in Parkinson's disease. Nature Med. 8, 600–606 (2002).This is the first study to show that dopamine contributes to the toxicity of mutant α-synuclein using primary human mesencephalic cultures.
  CAS PubMed Google Scholar
• Hartmann, A. & Hirsch, E. C. Parkinson's disease. The apoptosis hypothesis revisited. Adv. Neurol. 86, 143–153 (2001).
  CAS PubMed Google Scholar
• Lee, C. S. et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann. Neurol. 47, 493–503 (2000).
  CAS PubMed Google Scholar
• da Costa, C. A., Ancolio, K. & Checler, F. Wild-type but not Parkinson's disease-related Ala-53 → Thr mutant α-synuclein protects neuronal cells from apoptotic stimuli. J. Biol. Chem. 275, 24065–24069 (2000).
  CAS PubMed Google Scholar
• Hashimoto, M. et al. α-synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. J. Biol. Chem. 277, 11465–11472 (2002).
  CAS PubMed Google Scholar
• Seo, J. H. et al. α-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J. 5 September 2002 (doi:10.1096/fj.02–0041fje).
• Davidson, W. S., Jonas, A., Clayton, D. F. & George, J. M. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443–9449 (1998).
  CAS PubMed Google Scholar
• Jensen, P. H., Nielsen, M. H., Jakes, R., Dotti, C. G. & Goedert, M. Binding of α-synuclein to rat brain vesicles is abolished by familial Parkinson's disease mutation. J. Biol. Chem. 273, 26292–26294 (1998).
  CAS PubMed Google Scholar
• Jo, E., Fuller, N., Rand, R. P., St George-Hyslop, P. & Fraser, P. E. Defective membrane interactions of familial Parkinson's disease mutant A30P α-synuclein. J. Mol. Biol. 315, 799–807 (2002).
  CAS PubMed Google Scholar
• Jo, E., McLaurin, J. A., Yip, C. M., St George-Hyslop, P. H. & Fraser, P. α-synuclein membrane interactions and lipid specificity. J. Biol. Chem. 275, 34328–34334 (2000).
  CAS PubMed Google Scholar
• Jenco, J. M., Rawlingson, A., Daniels, B. & Morris, A. J. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by α- and β-synuclein. Biochemistry 37, 4901–4909 (1998).A seminal study indicating that an important housekeeping function of the synucleins might be to modulate PLD2 activity.
  CAS PubMed Google Scholar
• Ahn, B. H. et al. α-synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells. J. Biol. Chem. 277, 12334–12342 (2002).
  CAS PubMed Google Scholar
• Cockcroft, S. Signalling roles of mammalian phospholipase D1 and D2. Cell. Mol. Life Sci. 58, 1674–1687 (2001).
  CAS PubMed Google Scholar
• Liscovitch, M., Czarny, M., Fiucci, G. & Tang, X. Phospholipase D: molecular and cell biology of a novel gene family. Biochem. J. 345, 401–415 (2000).
  CAS PubMed PubMed Central Google Scholar
• Lotharius, J. & Brundin, P. Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum. Mol. Genet. 11, 2395–2407 (2002).
  CAS PubMed Google Scholar
• Murphy, D. D., Rueter, S. M., Trojanowski, J. Q. & Lee, V. M. Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J. Neurosci. 20, 3214–2310 (2000).A study showing that deletion of wild-type α-synuclein using antisense oligonucleotide technology reduces the number of vesicles in the reserve pool, indicating that α-synuclein might regulate vesicle biogenesis.
  CAS PubMed PubMed Central Google Scholar
• Kahle, P. J. et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant α-synuclein in human and transgenic mouse brain. J. Neurosci. 20, 6365–6373 (2000).
  CAS PubMed PubMed Central 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).
  CAS PubMed Google Scholar
• Matsuoka, Y. & Vila, M. 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).
  CAS PubMed 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).
  CAS PubMed Google Scholar