Alpha-synuclein: normal function and role in neurodegenerative diseases.

Synucleins are a family of small, highly charged proteins expressed predominantly in neurons. Since their discovery and characterization during the last decade, much has been learned about their structure, potential functions, interactions with other proteins, and roles in disease. One of these proteins, alpha-synuclein (alpha-syn), is the major building block of pathological inclusions that characterize many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation type 1 (NBIA-1), which collectively are termed synucleinopathies. Furthermore, genetic and biological studies support a role for alpha-syn in the pathophysiology of these diseases. Therefore, research must be continued in order to better understand the functions of the synuclein proteins under normal physiological conditions as well as their role in diseases.

[1]  Shawn K. Westaway,et al.  A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome , 2001, Nature Genetics.

[2]  Nigel J. Cairns,et al.  Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies , 1998, Neuroscience Letters.

[3]  Jimi Adu,et al.  Persyn, a member of the synuclein family, influences neurofilament network integrity , 1998, Nature Neuroscience.

[4]  Makoto Hashimoto,et al.  β-Synuclein Inhibits α-Synuclein Aggregation A Possible Role as an Anti-Parkinsonian Factor , 2001, Neuron.

[5]  C. Tanner,et al.  Environmental factors and Parkinson's disease , 1989, Neurology.

[6]  J Q Trojanowski,et al.  A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly* , 2001, The Journal of Biological Chemistry.

[7]  John Q. Trojanowski,et al.  Induction of α-Synuclein Aggregation by Intracellular Nitrative Insult , 2001, The Journal of Neuroscience.

[8]  Jeffrey L. Cummings,et al.  Dementia with Lewy bodies , 1996, Neurology.

[9]  P. Worley,et al.  Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions , 1999, Nature Genetics.

[10]  J. Trojanowski,et al.  Epitopes located in spatially separate domains of each neurofilament subunit are present in parkinson's disease lewy bodies , 1991, The Journal of comparative neurology.

[11]  Patrick R. Hof,et al.  Tau protein isoforms, phosphorylation and role in neurodegenerative disorders 1 1 These authors contributed equally to this work. , 2000, Brain Research Reviews.

[12]  L. Kurland,et al.  A case‐control study of smoking habits, dementia, and other illnesses in idiopathic Parkinson's disease , 1987, Neurology.

[13]  R. Palazzo,et al.  Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. , 2001, Cell motility and the cytoskeleton.

[14]  Akihiko Iwai,et al.  The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system , 1995, Neuron.

[15]  B. Giasson,et al.  Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. , 2000, The Journal of biological chemistry.

[16]  Y. Ihara,et al.  Lewy bodies are ubiquitinated , 1988, Acta Neuropathologica.

[17]  E. Masliah,et al.  Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Al-Mehdi,et al.  Peroxynitrite‐mediated oxidative protein modifications , 1995, FEBS letters.

[19]  S. Shioda,et al.  Distribution of PNP 14 (β‐synuclein) in neuroendocrine tissues: Localization in Sertoli cells , 1998, Molecular reproduction and development.

[20]  P J McLean,et al.  Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson's disease-linked mutations. , 2000, The Journal of biological chemistry.

[21]  J. Culvenor,et al.  α‐Synuclein Immunoisolation of Glial Inclusions from Multiple System Atrophy Brain Tissue Reveals Multiprotein Components , 1999, Journal of neurochemistry.

[22]  G. Anantharamaiah,et al.  The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. , 1992, Journal of lipid research.

[23]  R. Tripathi,et al.  Clinicopathologic correlation and pathogenesis of ocular and central nervous system manifestations in Hallervorden-Spatz syndrome , 2004, Acta Neuropathologica.

[24]  J. Parkinson.  An Essay on the Shaking Palsy , 2002 .

[25]  R. Perrin,et al.  Interaction of human alpha-Synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis. , 2000, The Journal of biological chemistry.

[26]  D. Galasko,et al.  Neocortical Lewy Body Counts Correlate with Dementia in the Lewy Body Variant of Alzheimer's Disease , 1996, Journal of neuropathology and experimental neurology.

[27]  P. Lansbury,et al.  Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. , 2002, Journal of molecular biology.

[28]  Christian Haass,et al.  Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant α-Synuclein in Human and Transgenic Mouse Brain , 2000, The Journal of Neuroscience.

[29]  S. Murayama,et al.  Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for α-synuclein , 1998, Neurology.

[30]  R. Nussbaum,et al.  α-Synuclein Is Phosphorylated by Members of the Src Family of Protein-tyrosine Kinases* , 2001, The Journal of Biological Chemistry.

[31]  John A. Murphy,et al.  Reactions of oxyl radicals with DNA. , 1995, Free radical biology & medicine.

[32]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[33]  D. Eliezer,et al.  Conformational properties of alpha-synuclein in its free and lipid-associated states. , 2001, Journal of molecular biology.

[34]  J. Trojanowski,et al.  Tau and α-Synuclein Pathology in Amygdala of Parkinsonism-Dementia Complex Patients of Guam , 2002 .

[35]  Makoto Hashimoto,et al.  Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease , 1998, Brain Research.

[36]  G. Irvine,et al.  The N‐terminal region of non‐Aβ component of Alzheimer's Disease amyloid is responsible for its tendency to assume β‐sheet and aggregate to form fibrils , 1998 .

[37]  G. Withers,et al.  Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. , 1997, Brain research. Developmental brain research.

[38]  H. Budka,et al.  Neuroaxonal dystrophy combined with diffuse Lewy body disease in a young adult. , 1993, Clinical neuropathology.

[39]  A. Sidhu,et al.  Attenuation of dopamine transporter activity by α-synuclein , 2003, Neuroscience Letters.

[40]  Lipton Ra,et al.  Letter: Factor VIII. , 1973, Lancet.

[41]  K. Wakabayashi,et al.  Widespread occurrence of α‐synuclein/NACP‐immunoreactive neuronal inclusions in juvenileand adult‐onset Hallervorden–Spatz diseasewith Lewy bodies , 1999 .

[42]  C. Lavedan.  The synuclein family. , 1998, Genome research.

[43]  J. Langston,et al.  Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine exposure , 1999, Annals of neurology.

[44]  P. Lansbury,et al.  Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson’s disease? , 2000, Nature Cell Biology.

[45]  Colin L. Masters,et al.  α-Synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease β-amyloid plaque cores , 1999, Neuroscience Letters.

[46]  Carlo Colosimo,et al.  Multiple system atrophy , 2004, The Lancet Neurology.

[47]  G. E. Smith,et al.  REM sleep behavior disorder and degenerative dementia , 1998, Neurology.

[48]  H. Niznik,et al.  Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  L. Petrucelli,et al.  α-Synuclein Shares Physical and Functional Homology with 14-3-3 Proteins , 1999, The Journal of Neuroscience.

[50]  A. Lees,et al.  A clinicopathologic study of 100 cases of Parkinson's disease. , 1993, Archives of neurology.

[51]  B. Giasson,et al.  Effects of Oxidative and Nitrative Challenges on α-Synuclein Fibrillogenesis Involve Distinct Mechanisms of Protein Modifications* , 2003, Journal of Biological Chemistry.

[52]  L. Forno,et al.  Neuropathology of Parkinson's Disease , 1996, Journal of neuropathology and experimental neurology.

[53]  J. Trojanowski,et al.  Mutant and Wild Type Human α-Synucleins Assemble into Elongated Filaments with Distinct Morphologies in Vitro * , 1999, The Journal of Biological Chemistry.

[54]  A. Davies,et al.  Chicken synucleins: cloning and expression in the developing embryo , 2000, Mechanisms of Development.

[55]  R. G. Lee,et al.  Parkinson's disease , 1993, Neurology.

[56]  P. Lansbury,et al.  The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease? , 1995, Chemistry & biology.

[57]  K. Kosaka,et al.  Dementia with Lewy bodies. , 1996, Current opinion in neurology.

[58]  Peter T. Lansbury,et al.  Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease , 1998, Nature Medicine.

[59]  M. Citron,et al.  Parkinson's Disease-associated α-Synuclein Is More Fibrillogenic than β- and γ-Synuclein and Cannot Cross-seed Its Homologs* , 2000, The Journal of Biological Chemistry.

[60]  R. Anthony Crowther,et al.  Synthetic filaments assembled from C‐terminally truncated α‐synuclein , 1998 .

[61]  K. Kashiwado,et al.  Pure autonomic failure in association with human α-synucleinopathy , 2000, Neuroscience Letters.

[62]  J. Payton,et al.  Protein-protein interactions of alpha-synuclein in brain homogenates and transfected cells. , 2001, Brain research. Molecular brain research.

[63]  E. Gilbert-Barness,et al.  Osmiophilic deposits in cytosomes in Hallervorden-Spatz syndrome. , 1990, Pediatric Neurology.

[64]  D. Dickson,et al.  Pathology and Biology of the Lewy Body , 1993, Journal of neuropathology and experimental neurology.

[65]  Richard Paylor,et al.  Synaptic Vesicle Depletion Correlates with Attenuated Synaptic Responses to Prolonged Repetitive Stimulation in Mice Lacking α-Synuclein , 2002, The Journal of Neuroscience.

[66]  J. Trojanowski,et al.  Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. , 2000, Science.

[67]  Olaf Riess,et al.  AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease , 1998, Nature Genetics.

[68]  B. Boeve,et al.  Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. , 2000, Brain : a journal of neurology.

[69]  Peter T Lansbury,et al.  Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease. , 2003, Biochemistry.

[70]  Heidi Phillips,et al.  Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System , 2000, Neuron.

[71]  M. Goedert,et al.  Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. , 1995, Genomics.

[72]  Samuel M. Goldman,et al.  EPIDEMIOLOGY OF PARKINSON'S DISEASE , 1996, Neurologic Clinics.

[73]  R D ADAMS,et al.  STRIATO-NIGRAL DEGENERATION. , 1964, Journal of neuropathology and experimental neurology.

[74]  A. Graybiel,et al.  The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. , 1999, Brain : a journal of neurology.

[75]  I. Kanazawa,et al.  Superoxide dismutase-like immunoreactivity in spheroids in Hallervorden-Spatz disease , 1996, Acta Neuropathologica.

[76]  J. Trojanowski,et al.  The Expression of α-, β-, and γ-Synucleins in Olfactory Mucosa from Patients with and without Neurodegenerative Diseases , 1999, Experimental Neurology.

[77]  K. Tipton,et al.  Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds , 1993, Journal of neurochemistry.

[78]  J Q Trojanowski,et al.  Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. , 1998, The American journal of pathology.

[79]  A. van Harreveld,et al.  The nature of postasphyxial rigidity examined by intracellular recording from motoneurons. , 1967, Experimental neurology.

[80]  David F. Clayton,et al.  Characterization of a novel protein regulated during the critical period for song learning in the zebra finch , 1995, Neuron.

[81]  J. Trojanowski,et al.  Expression of α-, β-, and γ-synuclein in glial tumors and medulloblastomas , 2003, Acta Neuropathologica.

[82]  H. Ischiropoulos.  Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. , 1998, Archives of biochemistry and biophysics.

[83]  Nancy A. Jenkins,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 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[84]  K. Arima,et al.  Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy , 2004, Acta Neuropathologica.

[85]  D L Price,et al.  Basal forebrain neurons in the dementia of Parkinson disease , 1983, Annals of neurology.

[86]  J. Trojanowski,et al.  Neuronal α-Synucleinopathy with Severe Movement Disorder in Mice Expressing A53T Human α-Synuclein , 2002, Neuron.

[87]  P. S. St George-Hyslop,et al.  α-Synuclein Membrane Interactions and Lipid Specificity* , 2000, The Journal of Biological Chemistry.

[88]  P. Lansbury,et al.  Accelerated Oligomerization by Parkinson's Disease Linked α‐Synuclein Mutants , 2000 .

[89]  K. Iwanaga,et al.  Lewy body–type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases , 1999, Neurology.

[90]  P. Lansbury,et al.  Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. , 2000, Biochemistry.

[91]  B. Freeman,et al.  Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. , 1991, The Journal of biological chemistry.

[92]  S. Fahn,et al.  Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse lewy body disease and 34 pathologically confirmed cases of parkinson's disease , 1997, Neurology.

[93]  P. Højrup,et al.  α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356* , 1999, The Journal of Biological Chemistry.

[94]  C. Marsden,et al.  Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. , 1992, Brain : a journal of neurology.

[95]  P. Blumbergs,et al.  In Situ and in Vitro Study of Colocalization and Segregation of α-Synuclein, Ubiquitin, and Lipids in Lewy Bodies , 2000, Experimental Neurology.

[96]  E. Junn,et al.  Human α-Synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine , 2002, Neuroscience Letters.

[97]  Oswald Bumke,et al.  Handbuch der Neurologie , 1936 .

[98]  M. Citron,et al.  Both Familial Parkinson’s Disease Mutations Accelerate α-Synuclein Aggregation* , 1999, The Journal of Biological Chemistry.

[99]  B. Freeman,et al.  Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. , 1991, Archives of biochemistry and biophysics.

[100]  J Q Trojanowski,et al.  Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. , 1998, The American journal of pathology.

[101]  V. Uversky,et al.  Pesticides directly accelerate the rate of α‐synuclein fibril formation: a possible factor in Parkinson's disease , 2001, FEBS letters.

[102]  V. Uversky,et al.  Nitration inhibits fibrillation of human α‐synuclein in vitro by formation of soluble oligomers , 2003 .

[103]  C. Marsden,et al.  HOW COMMON IS DEMENTIA IN PARKINSON'S DISEASE? , 1984, The Lancet.

[104]  C. Hertzman,et al.  Parkinson's disease: a case-control study of occupational and environmental risk factors. , 1990, American journal of industrial medicine.

[105]  R. Marttila,et al.  DEMENTIA IN PARKINSON'S DISEASE , 1976, Acta neurologica Scandinavica.

[106]  M. Goedert,et al.  Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson’s Disease Mutation* , 1998, The Journal of Biological Chemistry.

[107]  J. Trojanowski,et al.  Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary , 2000, Cancer.

[108]  M. Kupersmith,et al.  Dementia in Parkinson disease , 1979, Annals of neurology.

[109]  Shigeo Hirai,et al.  NACP/α-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy , 1998, Acta Neuropathologica.

[110]  W. Engel,et al.  Novel Immunolocalization of α‐Synuclein in Human Muscle of Inclusion‐Body Myositis, Regenerating and Necrotic Muscle Fibers, and at Neuromuscular Junctions , 2000, Journal of neuropathology and experimental neurology.

[111]  B. Giasson,et al.  Chaperone‐like activity of synucleins , 2000, FEBS letters.

[112]  J. Langston,et al.  Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. , 1983, Science.

[113]  S. Scarlata,et al.  Membrane binding and self-association of alpha-synucleins. , 2001, Biochemistry.

[114]  T. Taylor,et al.  Homozygosity mapping of Hallervorden–Spatz syndrome to chromosome 20p12.3–p13 , 1996, Nature Genetics.

[115]  Patrik Brundin,et al.  Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein , 2002, Nature Reviews Neuroscience.

[116]  S. Kawanishi,et al.  Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide , 1995, FEBS letters.

[117]  N. Quinn,et al.  Multiple system atrophy: A review of 203 pathologically proven cases , 1997, Movement disorders : official journal of the Movement Disorder Society.

[118]  E. Masliah,et al.  NACP, a synaptic protein involved in Alzheimer's disease, is differentially regulated during megakaryocyte differentiation. , 1997, Biochemical and biophysical research communications.

[119]  A. Cederbaum,et al.  Synergistic interactions between NADPH-cytochrome P-450 reductase, paraquat, and iron in the generation of active oxygen radicals. , 1989, Biochemical pharmacology.

[120]  R. Mindham,et al.  A controlled study of dementia in Parkinson's disease. , 1982, Journal of neurology, neurosurgery, and psychiatry.

[121]  D. Perl,et al.  Accumulation of alpha-synuclein in autonomic nerves in pure autonomic failure , 2001, Neurology.

[122]  A. Dehejia,et al.  Identification, localization and characterization of the human γ-synuclein gene , 1998, Human Genetics.

[123]  J Kim,et al.  Copper(II)-induced self-oligomerization of alpha-synuclein. , 1999, The Biochemical journal.

[124]  Sid Gilman,et al.  Widespread Alterations of α-Synuclein in Multiple System Atrophy , 1999 .

[125]  N P Quinn,et al.  Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. , 1994, Brain : a journal of neurology.

[126]  J. Trojanowski,et al.  Synucleins Are Developmentally Expressed, and α-Synuclein Regulates the Size of the Presynaptic Vesicular Pool in Primary Hippocampal Neurons , 2000, The Journal of Neuroscience.

[127]  J. Trojanowski,et al.  Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. , 2000, The American journal of pathology.

[128]  J S Beckman,et al.  Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. , 1996, The American journal of physiology.

[129]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[130]  A. Davies,et al.  Persyn, a Member of the Synuclein Family, Has a Distinct Pattern of Expression in the Developing Nervous System , 1998, The Journal of Neuroscience.

[131]  D. Oppenheimer,et al.  Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. , 1969, Journal of neurology, neurosurgery, and psychiatry.

[132]  A. Davies,et al.  Organization, expression and polymorphism of the human persyn gene. , 1998, Human molecular genetics.

[133]  G. Xiao,et al.  Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. , 1997, Cancer research.

[134]  Peter T. Lansbury,et al.  Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct , 2001, Science.

[135]  M. Farrer,et al.  Lack of Nigral Pathology in Transgenic Mice Expressing Human α-Synuclein Driven by the Tyrosine Hydroxylase Promoter , 2001, Neurobiology of Disease.

[136]  A. Morris,et al.  Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. , 1998, Biochemistry.

[137]  J. Jeng,et al.  Environmental risk factors and Parkinson's disease , 1997, Neurology.

[138]  V. Uversky,et al.  Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. , 2001, The Journal of biological chemistry.

[139]  S. W. Lin,et al.  Protein damage and degradation by oxygen radicals. II. Modification of amino acids. , 1987, The Journal of biological chemistry.

[140]  Robert Burke,et al.  Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[141]  L. Wolfson,et al.  Antemortem diagnosis of diffuse Lewy body disease , 1990, Neurology.

[142]  J. Langston,et al.  Environmental Risk Factors and Parkinson's Disease: Selective Degeneration of Nigral Dopaminergic Neurons Caused by the Herbicide Paraquat , 2002, Neurobiology of Disease.

[143]  J. Cummings,et al.  Frequency of dementia in Parkinson disease. , 1996, Archives of neurology.

[144]  J. Trojanowski,et al.  Neurodegeneration with Brain Iron Accumulation, Type 1 Is Characterized by α-, β-, and γ-Synuclein Neuropathology , 2000 .

[145]  G. Glosser,et al.  Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease , 2000, Neurology.

[146]  R. Scheller,et al.  Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[147]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[148]  P. Lantos,et al.  Lewy bodies are located preferentially in limbic areas in diffuse Lewy body disease , 1996, Neuroscience Letters.

[149]  R. Swerdlow,et al.  Origin and functional consequences of the complex I defect in Parkinson's disease , 1996, Annals of neurology.

[150]  K. Kosaka,et al.  Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) , 1996, Neurology.

[151]  J. Dejerine,et al.  L'atrophie olivo-ponto-cerebelleuse , 1900 .

[152]  J. Trojanowski,et al.  α‐synuclein is developmentally expressed in cultured rat brain oligodendrocytes , 2000, Journal of neuroscience research.

[153]  Robert H. Perry,et al.  Senile dementia of Lewy body type A clinically and neuropathologically distinct form of Lewy body dementia in the elderly , 1990, Journal of the Neurological Sciences.

[154]  M. Farrer,et al.  Sensitization of Neuronal Cells to Oxidative Stress with Mutated Human α‐Synuclein , 2000 .

[155]  T. Iwatsubo,et al.  α‐Synuclein Inclusions in Amygdala in the Brains of Patients with the Parkinsonism‐Dementia Complex of Guam , 2000, Journal of neuropathology and experimental neurology.

[156]  J. Trojanowski,et al.  Neuropathology of synuclein aggregates , 2000, Journal of neuroscience research.

[157]  Kenneth F. Swaiman.  Hallervorden-Spatz syndrome and brain iron metabolism. , 1991 .

[158]  R. Jakes,et al.  Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of α‐synuclein protein implicated in Parkinson's disease , 1998, FEBS letters.

[159]  M. Hur,et al.  Expression Patterns of α-Synuclein in Human Hematopoietic Cells and in Drosophila at Different Developmental Stages , 2000 .

[160]  J. Trojanowski,et al.  Antibodies to α‐synuclein detect Lewy bodies in many Down's syndrome brains with Alzheimer's disease , 1999, Annals of neurology.

[161]  Donald E. Schmechel,et al.  Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease , 2003, Acta Neuropathologica.

[162]  R. Crowther,et al.  Intraneuronal filamentous tau protein and α-synuclein deposits in neurodegenerative diseases , 1998 .

[163]  C. Cross,et al.  Aromatic hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite , 1994, FEBS letters.

[164]  F. Checler,et al.  Wild-type but Not Parkinson's Disease-related Ala-53 → Thr Mutant α-Synuclein Protects Neuronal Cells from Apoptotic Stimuli* , 2000, The Journal of Biological Chemistry.

[165]  S. Nakajo,et al.  Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14) , 1993, Brain Research.

[166]  L. Thal,et al.  The Lewy body variant of Alzheimer's disease , 1990, Neurology.

[167]  A. Jonas,et al.  Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes* , 1998, The Journal of Biological Chemistry.

[168]  M. Citron,et al.  alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. , 1999, The Journal of biological chemistry.

[169]  W. Pryor,et al.  Peroxynitrite causes DNA nicks in plasmid pBR322. , 1995, Biochemical and biophysical research communications.

[170]  H. M. Zimmerman.  Progress in neuropathology , 1971 .

[171]  Y. C. Chang,et al.  Effects of paraquat on the substantia nigra of the wistar rats: neurochemical, histological, and behavioral studies. , 1996, Toxicology and applied pharmacology.

[172]  Peter L. Lantos,et al.  Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome) , 1989, Journal of the Neurological Sciences.

[173]  I. Kanazawa,et al.  Widespread expression of α-synuclein and τ immunoreactivity in Hallervorden–Spatz syndrome with protracted clinical course , 2000, Journal of the Neurological Sciences.

[174]  S. Nakajo,et al.  Distribution of phosphoneuroprotein 14 (PNP 14) in vertebrates: its levels as determined by enzyme immunoassay , 1996, Brain Research.

[175]  V. Tennyson,et al.  Phase and Electron Microscopic Observations of Lewy Bodies and Melanin Granules in the Substantia Nigra and Locus Caeruleus in Parkinson's Disease , 1965 .

[176]  K. Kosaka,et al.  Diffuse lewy body disease in Japan , 1990, Journal of Neurology.

[177]  R. Scheller,et al.  The rat brain synucleins; family of proteins transiently associated with neuronal membrane. , 1991, Brain research. Molecular brain research.

[178]  A. Lang,et al.  Parkinson's disease. First of two parts. , 1998, The New England journal of medicine.

[179]  L. Lipkin,et al.  DIFFUSE INTRACYTOPLASMIC GANGLIONIC INCLUSIONS (LEWY TYPE) ASSOCIATED WITH PROGRESSIVE DEMENTIA AND QUADRIPARESIS IN FLEXION , 1961, Journal of neuropathology and experimental neurology.

[180]  J. Trojanowski,et al.  A comparison of amyloid fibrillogenesis using the novel fluorescent compound K114 , 2003, Journal of neurochemistry.

[181]  J. Trojanowski,et al.  Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases , 2002, Annals of neurology.

[182]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[183]  R. Mayeux,et al.  Altered serotonin metabolism in depressed patients with Parkinson's disease , 1984, Neurology.

[184]  J. Exton.  Phospholipase D: enzymology, mechanisms of regulation, and function. , 1997, Physiological reviews.

[185]  P. Lansbury,et al.  Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[186]  H De Loof,et al.  Amphipathic helix motif: Classes and properties , 1990, Proteins.

[187]  C. C. Johnson,et al.  Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease. , 1999, Neurotoxicology.

[188]  K. Davis,et al.  Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions. , 2000, Archives of neurology.

[189]  H J Gundersen,et al.  The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[190]  A. Graybiel,et al.  The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. , 1999, Brain : a journal of neurology.

[191]  Michel Goedert,et al.  Identification of two distinct synucleins from human brain , 1994, FEBS letters.

[192]  J. Culvenor,et al.  α-synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy , 2003, Experimental Neurology.

[193]  P. Mcgeer,et al.  Myelin degeneration in multiple system atrophy detected by unique antibodies. , 1998, The American journal of pathology.

[194]  H. Ischiropoulos,et al.  Oxidative stress and nitration in neurodegeneration: cause, effect, or association? , 2003, The Journal of clinical investigation.

[195]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[196]  M. Hoehn,et al.  Parkinsonism , 1967, Neurology.

[197]  V. Uversky,et al.  Certain Metals Trigger Fibrillation of Methionine-oxidized α-Synuclein* , 2003, Journal of Biological Chemistry.

[198]  John Hardy,et al.  The A53T α-Synuclein Mutation Increases Iron-Dependent Aggregation and Toxicity , 2000, The Journal of Neuroscience.

[199]  V. Uversky,et al.  Methionine oxidation inhibits fibrillation of human α‐synuclein in vitro , 2002 .

[200]  S. Hammond,et al.  Phospholipase D Stimulates Release of Nascent Secretory Vesicles from the trans-Golgi Network , 1997, The Journal of cell biology.

[201]  P. Eriksson,et al.  Neonatal exposure to paraquat or MPTP induces permanent changes in striatum dopamine and behavior in adult mice. , 1993, Toxicology and applied pharmacology.

[202]  V. Uversky,et al.  Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. , 2001, Biochemistry.

[203]  S. Paik,et al.  Metal-Catalyzed Oxidation of α-Synuclein in the Presence of Copper(II) and Hydrogen Peroxide , 2000 .

[204]  J. Vickers,et al.  Localization of α-, β-, and γ-synuclein during neuronal development and alterations associated with the neuronal response to axonal trauma , 2003, Experimental Neurology.

[205]  G M SHY,et al.  A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. , 1960, Archives of neurology.

[206]  P. Blumbergs,et al.  Multiple-system atrophy: a new α-synuclein disease? , 1998, The Lancet.

[207]  A. Goldberg,et al.  PAN, the proteasome-activating nucleotidase from archaebacteria, is a protein-unfolding molecular chaperone , 2000, Nature Cell Biology.

[208]  E. Masliah,et al.  Non-A beta component of Alzheimer's disease amyloid (NAC) is amyloidogenic. , 1995, Biochemistry.

[209]  V. Uversky,et al.  The Herbicide Paraquat Causes Up-regulation and Aggregation of α-Synuclein in Mice , 2002, The Journal of Biological Chemistry.

[210]  Vladimir N. Uversky,et al.  Amino acid determinants of α‐synuclein aggregation: putting together pieces of the puzzle , 2002 .

[211]  J. Trojanowski,et al.  Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein , 2003, Science.

[212]  W. Gibb,et al.  Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body dementia). , 1987, Brain : a journal of neurology.

[213]  A. Davies,et al.  Developmentally regulated expression of persyn, a member of the synuclein family, in skin. , 1999, Experimental cell research.

[214]  M. Yoshimoto,et al.  NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[215]  Philip J. Langlais,et al.  Late‐onset Hallervorden‐Spatz disease presenting as familial parkinsonism , 1985, Neurology.

[216]  T. Hirabayashi,et al.  Expression of β-synuclein in normal human astrocytes , 2001 .

[217]  L. Thal,et al.  Genetic-Evidence That the Lewy Body Variant Is Indeed a Phenotypic Variant of Alzheimers-Disease , 1995, Brain and Cognition.

[218]  S. Nakajo,et al.  Cloning and Characterization of the cDNA Encoding a Novel Brain‐Specific 14‐kDa Protein , 1992, Journal of neurochemistry.

[219]  W. Nicklas,et al.  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. , 1985, Life sciences.

[220]  P. Lansbury,et al.  NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. , 1996, Biochemistry.

[221]  S. Shioda,et al.  Localization of phosphoneuroprotein 14 (PNP 14) and its mRNA expression in rat brain determined by immunocytochemistry and in situ hybridization. , 1994, Brain research. Molecular brain research.

[222]  Todd B. Sherer,et al.  An In Vitro Model of Parkinson's Disease: Linking Mitochondrial Impairment to Altered α-Synuclein Metabolism and Oxidative Damage , 2002, The Journal of Neuroscience.

[223]  T. Montine,et al.  Immunohistochemical and Biochemical Studies Demonstrate a Distinct Profile of α‐Synuclein Permutations in Multiple System Atrophy , 2000, Journal of neuropathology and experimental neurology.

[224]  J Q Trojanowski,et al.  Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. , 1991, The American journal of pathology.

[225]  L A Hansen,et al.  Clinical-neuropathological correlations in Alzheimer's disease and related dementias. , 1994, Archives of neurology.

[226]  B. Hyman,et al.  Nigral and Cortical Lewy Bodies and Dystrophic Nigral Neurites in Parkinson's Disease and Cortical Lewy Body Disease Contain α-synuclein Immunoreactivity , 1998, Journal of neuropathology and experimental neurology.

[227]  K. Marder,et al.  An estimate of the incidence of dementia in idiopathic Parkinson's disease , 1990, Neurology.

[228]  A. Dehejia,et al.  Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease , 1998, Molecular Psychiatry.

[229]  J Q Trojanowski,et al.  Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein , 1998, Annals of neurology.

[230]  J. Trojanowski,et al.  Differential Expression and Distribution of α-, β-, and γ-Synuclein in the Developing Human Substantia Nigra , 2001, Experimental Neurology.

[231]  L. Serpell,et al.  Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[232]  J. Trojanowski,et al.  A panel of epitope‐specific antibodies detects protein domains distributed throughout human α‐synuclein in lewy bodies of Parkinson's disease , 2000, Journal of neuroscience research.

[233]  A. Manning-Boğ,et al.  α-Synuclein Overexpression Protects against Paraquat-Induced Neurodegeneration , 2003, The Journal of Neuroscience.

[234]  S. Fahn,et al.  Pathologically diagnosed diffuse Lewy body disease and Parkinson's disease. Do the parkinsonian features differ? , 1996, Advances in neurology.

[235]  Theodore W Randolph,et al.  Oxidative dimer formation is the critical rate-limiting step for Parkinson's disease alpha-synuclein fibrillogenesis. , 2003, Biochemistry.

[236]  S. Padmaja,et al.  The reaction of no with superoxide. , 1993, Free radical research communications.

[237]  Kenji Kosaka,et al.  Lewy bodies in cerebral cortex. Report of three cases , 1978, Acta Neuropathologica.

[238]  V. Uversky,et al.  Evidence for a Partially Folded Intermediate in α-Synuclein Fibril Formation* , 2001, The Journal of Biological Chemistry.

[239]  J. Trojanowski,et al.  Concurrence of α-synuclein and tau brain pathology in the Contursi kindred , 2002, Acta Neuropathologica.

[240]  W. Honer,et al.  Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. , 1998, The American journal of pathology.

[241]  Hitoshi Takahashi,et al.  α-Synuclein immunoreactivity in normal and neoplastic Schwann cells , 2002, Acta Neuropathologica.

[242]  E. Myers,et al.  Finishing a whole-genome shotgun: Release 3 of the Drosophila melanogaster euchromatic genome sequence , 2002, Genome Biology.

[243]  Sarah J. Tabrizi,et al.  Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity , 2000 .

[244]  P. Mitchell,et al.  The Mechanism of Proton Translocation in Reversible Proton-Translocating Adenosine Triphosphatases , 1974 .

[245]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[246]  F. Jiménez-Jiménez,et al.  Exposure to well water and pesticides in Parkinson's disease: A case‐control study in the madrid area , 1992, Movement disorders : official journal of the Movement Disorder Society.

[247]  J. Cummings,et al.  The occurrence of depression in Parkinson's disease. A community-based study. , 1996, Archives of neurology.

[248]  D. Clayton,et al.  Synucleins in synaptic plasticity and neurodegenerative disorders , 1999, Journal of neuroscience research.

[249]  Susan E Daniel,et al.  Characterisation of isolated α-synuclein filaments from substantia nigra of Parkinson's disease brain , 2000, Neuroscience Letters.

[250]  W. Halliday.  The nosology of Hallervorden-Spatz disease , 1995, Journal of the Neurological Sciences.

[251]  Todd B. Sherer,et al.  Subcutaneous Rotenone Exposure Causes Highly Selective Dopaminergic Degeneration and α-Synuclein Aggregation , 2003, Experimental Neurology.

[252]  N P Quinn,et al.  Clinicopathological study of 35 cases of multiple system atrophy. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[253]  P. S. St George-Hyslop,et al.  Defective membrane interactions of familial Parkinson's disease mutant A30P α-synuclein , 2002 .

[254]  C. C. Johnson,et al.  The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living , 1998, Neurology.

[255]  G. Campanella,et al.  Ecogenetics of Parkinson's Disease: Prevalence and Environmental Aspects in Rural Areas , 1987, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[256]  J. Satoh,et al.  Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy , 2004, Acta Neuropathologica.

[257]  E. Dooling,et al.  Hallervorden-Spatz syndrome. , 1974, Archives of neurology.

[258]  A. Barbeau,et al.  Environmental and genetic factors in the etiology of Parkinson's disease. , 1987, Advances in neurology.

[259]  B. Hyman,et al.  Disordered proteins in dementia , 2002, Annals of medicine.

[260]  P. Axelsen,et al.  Role of α-Synuclein Carboxy-Terminus on Fibril Formation in Vitro† , 2003 .

[261]  V. Lee,et al.  Are Ubiquitination Pathways Central to Parkinson's Disease? , 2003, Cell.

[262]  J. Benovic,et al.  Synucleins Are a Novel Class of Substrates for G Protein-coupled Receptor Kinases* , 2000, The Journal of Biological Chemistry.