Parkinson disease: from pathology to molecular disease mechanisms

Agid, 1998, Levodopa: is toxicity a myth?, Neurology, 50, 858, 10.1212/WNL.50.4.858 Alvarez-Erviti, 2010, Chaperone-mediated autophagy markers in Parkinson disease brains, Arch. Neurol., 67, 1464, 10.1001/archneurol.2010.198 Ambani, 1975, Brain peroxidase and catalase in Parkinson disease, Arch. Neurol., 32, 114, 10.1001/archneur.1975.00490440064010 Ascherio, 2009, Urate as a predictor of the rate of clinical decline in Parkinson disease, Arch. Neurol., 66, 1460, 10.1001/archneurol.2009.247 Ascherio, 2009, Use of antihypertensives and the risk of Parkinson disease, Neurology, 72, 578, 10.1212/01.wnl.0000344171.22760.24 Berg, 2012, Defining at-risk populations for Parkinson's disease: lessons from ongoing studies, Mov. Disord, 27, 656, 10.1002/mds.24985 Betarbet, 2000, Chronic systemic pesticide exposure reproduces features of Parkinson's disease, Nat. Neurosci., 3, 1301, 10.1038/81834 Bevan, 2002, Move to the rhythm: oscillations in the subthalamic nucleus–external globus pallidus network, Trends Neurosci., 25, 525, 10.1016/S0166-2236(02)02235-X Blesa, 2012, Classic and new animal models of Parkinson's disease, J. Biomed. Biotechnol., 2012, 845618, 10.1155/2012/845618 Braak, 2006, Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology, Neurosci. Lett, 396, 67, 10.1016/j.neulet.2005.11.012 Braak, 2003, Staging of brain pathology related to sporadic Parkinson's disease, Neurobiol. Aging, 24, 197, 10.1016/S0197-4580(02)00065-9 Bukhatwa, 2010, The effects of dose and route of administration of PSI on behavioural and biochemical indices of neuronal degeneration in the rat brain, Brain Res, 1354, 236, 10.1016/j.brainres.2010.07.060 Chaudhuri, 2009, Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment, Lancet Neurol., 8, 464, 10.1016/S1474-4422(09)70068-7 Chen, 2001, Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease, J. Neurosci., 21, RC143, 10.1523/JNEUROSCI.21-10-j0001.2001 Cipriani, 2010, Urate: a novel biomarker of Parkinson's disease risk, diagnosis and prognosis, Biomark. Med., 4, 701, 10.2217/bmm.10.94 Clement, 2002, The cytotoxicity of dopamine may be an artefact of cell culture, J. Neurochem., 81, 414, 10.1046/j.1471-4159.2002.00802.x Dawson, 2007, Unraveling the role of defective genes in Parkinson's disease, Parkinsonism Relat. Disord, 13, S248, 10.1016/S1353-8020(08)70010-5 Dehay, 2010, Pathogenic lysosomal depletion in Parkinson's disease, J. Neurosci., 30, 12535, 10.1523/JNEUROSCI.1920-10.2010 Dehay, 2012, Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration, Proc. Natl. Acad. Sci. USA, 109, 9611, 10.1073/pnas.1112368109 Del, 2002, Where does Parkinson disease pathology begin in the brain?, J. Neuropathol. Exp. Neurol., 61, 413, 10.1093/jnen/61.5.413 Dickson, 2009, Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria, Lancet Neurol., 8, 1150, 10.1016/S1474-4422(09)70238-8 Dobbs, 1999, Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism, Acta Neurol. Scand., 100, 34, 10.1111/j.1600-0404.1999.tb00721.x Dunning, 2012, Can Parkinson's disease pathology be propagated from one neuron to another?, Prog. Neurobiol., 97, 205, 10.1016/j.pneurobio.2011.11.003 Duty, 2011, Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease, Br. J. Pharmacol, 164, 1357, 10.1111/j.1476-5381.2011.01426.x Elstner, 2011, Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death, Acta Neuropathol., 122, 75, 10.1007/s00401-011-0828-9 Fahn, 2005, Does levodopa slow or hasten the rate of progression of Parkinson's disease?, J. Neurol., 252, IV37 Findley, 2007, The economic impact of Parkinson's disease, Parkinsonism Relat. Disord., 13, S8, 10.1016/j.parkreldis.2007.06.003 Fujishiro, 2008, Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease, Mov. Disord, 23, 1085, 10.1002/mds.21989 Galter, 2010, MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease, Genes Brain Behav., 9, 173, 10.1111/j.1601-183X.2009.00542.x Gegg, 2012, Glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains, Ann. Neurol., 72, 455, 10.1002/ana.23614 Giasson, 2000, Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions, Science, 290, 985, 10.1126/science.290.5493.985 Glinka, 1997, Mechanism of 6-hydroxydopamine neurotoxicity, J. Neural Transm. Suppl., 50, 55, 10.1007/978-3-7091-6842-4_7 Goedert, 2001, Parkinson's disease and other alpha-synucleinopathies, Clin. Chem. Lab. Med., 39, 308, 10.1515/CCLM.2001.047 Goedert, 2010, The propagation of prion-like protein inclusions in neurodegenerative diseases, Trends Neurosci., 33, 317, 10.1016/j.tins.2010.04.003 Goedert, 1998, Lewy body diseases and multiple system atrophy as alpha-synucleinopathies, Mol. Psychiatry, 3, 462, 10.1038/sj.mp.4000458 Graham, 1978, Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones, Mol. Pharmacol, 14, 633 Grunblatt, 2004, Gene expression profiling of parkinsonian substantia nigra pars compacta: alterations in ubiquitin–proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes, J. Neural Transm., 111, 1543, 10.1007/s00702-004-0212-1 Gu, 1998, transmission of the mitochondrial defect in Parkinson's disease, Ann. Neurol., 44, 177, 10.1002/ana.410440207 Gupta, 2008, What causes cell death in Parkinson's disease?, Ann. Neurol., 64, S3 Hamza, 2010, Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease, Nat. Genet., 42, 781, 10.1038/ng.642 Hardy, 2010, Genetic analysis of pathways to Parkinson disease, Neuron, 68, 201, 10.1016/j.neuron.2010.10.014 Hattori, 2000, Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease, J. Neural Transm. Suppl., 60, 101 Hernandez-Romero, 2012, Peripheral inflammation increases the deleterious effect of CNS inflammation on the nigrostriatal dopaminergic system, Neurotoxicology, 33, 347, 10.1016/j.neuro.2012.01.018 Herrera, 2000, The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system, Neurobiol. Dis., 7, 429, 10.1006/nbdi.2000.0289 Hirsch, 2003, The role of glial reaction and inflammation in Parkinson's disease, Ann. N. Y. Acad. Sci., 991, 214, 10.1111/j.1749-6632.2003.tb07478.x Hoglinger, 2003, Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats, J. Neurochem., 84, 491, 10.1046/j.1471-4159.2003.01533.x Houlden, 2012, The genetics and neuropathology of Parkinson's disease, Acta Neuropathol., 124, 325, 10.1007/s00401-012-1013-5 Hovelso, 2012, Therapeutic potential of metabotropic glutamate receptor modulators, Curr. Neuropharmacol., 10, 12, 10.2174/157015912799362805 Hwang, 2003, Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice, Brain Res. Mol. Brain Res., 114, 123, 10.1016/S0169-328X(03)00162-1 Hyun, 2003, Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins, J. Neurochem., 86, 363, 10.1046/j.1471-4159.2003.01841.x Hyun, 2005, Effect of overexpression of wild-type or mutant parkin on the cellular response induced by toxic insults, J. Neurosci. Res., 82, 232, 10.1002/jnr.20638 Hyun, 2002, Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome, J. Biol. Chem., 277, 28572, 10.1074/jbc.M200666200 Ikeda, 1992, Search for neurotoxins structurally related to 1-methyl-4-phenylpyridine (MPP+) in the pathogenesis of Parkinson's disease, Brain Res, 575, 285, 10.1016/0006-8993(92)90092-N Inden, 2011, Parkinsonian rotenone mouse model: reevaluation of long-term administration of rotenone in C57BL/6 mice, Biol. Pharm. Bull., 34, 92, 10.1248/bpb.34.92 International Parkinson's Disease Genomic Consortium. A two-stage meta-analysis identifies several new loci for Parkinson's disease. PLoS Genet. 7:e1002142; 2011. Iravani, 2005, The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation, Eur. J. Neurosci., 22, 317, 10.1111/j.1460-9568.2005.04220.x Iravani, 2012, Lipopolysaccharide-induced nigral inflammation leads to increased IL-1beta tissue content and expression of astrocytic glial cell line-derived neurotrophic factor, Neurosci. Lett., 510, 138, 10.1016/j.neulet.2012.01.022 Jankovic, 2008, Parkinson's disease: clinical features and diagnosis, J. Neurol. Neurosurg. Psychiatry, 79, 368, 10.1136/jnnp.2007.131045 Jellinger, 2012, Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts, Mov. Disord, 27, 8, 10.1002/mds.23795 Jenner, 2004, Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson's disease, Neurology, 63, S13, 10.1212/WNL.63.7_suppl_2.S13 Jenner, 2003, Oxidative stress in Parkinson's disease, Ann. Neurol., 53, S26, 10.1002/ana.10483 Jenner, 2011, Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline, Mov. Disord, 26, 2316, 10.1002/mds.23926 Jenner, 2006, The pathogenesis of cell death in Parkinson's disease, Neurology, 66, S24, 10.1212/WNL.66.10_suppl_4.S24 Jenner, 1998, Understanding cell death in Parkinson's disease, Ann. Neurol., 44, S72, 10.1002/ana.410440712 Jenner, 1992, New insights into the cause of Parkinson's disease, Neurology, 42, 2241, 10.1212/WNL.42.12.2241 Jiang, 2005, Age-dependent dopaminergic dysfunction in Nurr1 knockout mice, Exp. Neurol., 191, 154, 10.1016/j.expneurol.2004.08.035 Johnson, 2009, Glutamate receptors as therapeutic targets for Parkinson's disease. CNS Neurol, Disord. Drug Targets, 8, 475, 10.2174/187152709789824606 Kalaitzakis, 2008, The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of alpha-synuclein staging, Neuropathol. Appl. Neurobiol., 34, 284, 10.1111/j.1365-2990.2007.00923.x Kempster, 2010, Relationships between age and late progression of Parkinson's disease: a clinico-pathological study, Brain, 133, 1755, 10.1093/brain/awq059 Kenborg, 2012, Parkinson's disease and other neurodegenerative disorders among welders: a Danish cohort study, Mov. Disord, 27, 1283, 10.1002/mds.25125 Kitada, 2009, Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice, J. Neurochem., 111, 696, 10.1111/j.1471-4159.2009.06350.x Kiyohara, 2011, Cigarette smoking and Parkinson's disease: a meta-analysis, Fukuoka Igaku Zasshi, 102, 254 Kordower, 2006, Failure of proteasome inhibitor administration to provide a model of Parkinson's disease in rats and monkeys, Ann. Neurol., 60, 264, 10.1002/ana.20935 Langston, 2006, The Parkinson's complex: parkinsonism is just the tip of the iceberg, Ann. Neurol., 59, 591, 10.1002/ana.20834 Lannuzel, 2006, Is atypical parkinsonism in the Caribbean caused by the consumption of Annonacae?, J. Neural Transm. Suppl., 70, 153, 10.1007/978-3-211-45295-0_24 Lannuzel, 2003, The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism, Neuroscience, 121, 287, 10.1016/S0306-4522(03)00441-X Lee, 2010, Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease, Nat. Med, 16, 998, 10.1038/nm.2199 Lee, 1993, Tau proteins are abnormally expressed in olfactory epithelium of Alzheimer patients and developmentally regulated in human fetal spinal cord, Exp. Neurol., 121, 93, 10.1006/exnr.1993.1074 Lee, 2001, Effect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production, J. Neurochem., 78, 32, 10.1046/j.1471-4159.2001.00416.x Lee, 2001, Effect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production, J. Neurochem., 78, 32, 10.1046/j.1471-4159.2001.00416.x Lehman, 2012, Neurodegenerative causes of death among retired National Football League players, Neurology, 79, 1970, 10.1212/WNL.0b013e31826daf50 Liu, 2011, Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models, Hum. Mol. Genet, 20, 3933, 10.1093/hmg/ddr312 Magen, 2010, Genetic mouse models of Parkinson's disease: the state of the art, Prog. Brain Res., 184, 53, 10.1016/S0079-6123(10)84004-X Mandel, 2005, Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives, Brain Res. Brain Res. Rev., 48, 379, 10.1016/j.brainresrev.2004.12.027 Mann, 1992, Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease, Brain, 115, 333, 10.1093/brain/115.2.333 Manning-Bog, 2006, Lack of nigrostriatal pathology in a rat model of proteasome inhibition, Ann. Neurol., 60, 256, 10.1002/ana.20938 Marin, 2011, In vivo 6-OHDA-induced neurodegeneration and nigral autophagic markers expression, Neurochem. Int., 58, 521, 10.1016/j.neuint.2011.01.010 Matsui, 2010, Proteasome inhibition in medaka brain induces the features of Parkinson's disease, J. Neurochem., 115, 178, 10.1111/j.1471-4159.2010.06918.x Mazzulli, 2011, Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies, Cell, 146, 37, 10.1016/j.cell.2011.06.001 McCormack, 2002, Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat, Neurobiol. Dis., 10, 119, 10.1006/nbdi.2002.0507 McDowell, 2012, Animal models of the non-motor features of Parkinson's disease, Neurobiol. Dis., 46, 597, 10.1016/j.nbd.2011.12.040 McGeer, 1988, Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains, Neurology, 38, 1285, 10.1212/WNL.38.8.1285 McGeer, 2003, Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, Ann. Neurol., 54, 599, 10.1002/ana.10728 McNaught, 2002, Proteasome inhibition causes nigral degeneration with inclusion bodies in rats, Neuroreport, 13, 1437, 10.1097/00001756-200208070-00018 McNaught, 1999, Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures, J. Neurochem, 73, 2469, 10.1046/j.1471-4159.1999.0732469.x McNaught, 2000, Dysfunction of rat forebrain astrocytes in culture alters cytokine and neurotrophic factor release, Neurosci. Lett., 285, 61, 10.1016/S0304-3940(00)00982-4 McNaught, 2001, Proteasomal function is impaired in substantia nigra in Parkinson's disease, Neurosci. Lett., 297, 191, 10.1016/S0304-3940(00)01701-8 McNaught, 2002, Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures, J. Neurochem., 81, 301, 10.1046/j.1471-4159.2002.00821.x McNaught, 2004, Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease, Ann. Neurol., 56, 149, 10.1002/ana.20186 McNaught, 2002, Aggresome-related biogenesis of Lewy bodies, Eur. J. Neurosci., 16, 2136, 10.1046/j.1460-9568.2002.02301.x Miklossy, 2006, Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys, Exp. Neurol., 197, 275, 10.1016/j.expneurol.2005.10.034 Miwa, 2006, Intragastric proteasome inhibition induces alpha-synuclein-immunopositive aggregations in neurons in the dorsal motor nucleus of the vagus in rats, Neurosci. Lett, 401, 146, 10.1016/j.neulet.2006.03.003 Mizuno, 1994, An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson's disease, Ann. Neurol., 35, 204, 10.1002/ana.410350212 Morrish, 2003, How valid is dopamine transporter imaging as a surrogate marker in research trials in Parkinson's disease?, Mov. Disord, 18, S63, 10.1002/mds.10581 Muzerengi, 2007, Non-motor symptoms: identification and management, Parkinsonism Relat. Disord., 13, S450, 10.1016/S1353-8020(08)70048-8 Nalls, 2011, Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies, Lancet, 377, 641, 10.1016/S0140-6736(10)62345-8 Olanow, 2009, Can we achieve neuroprotection with currently available anti-parkinsonian interventions?, Neurology, 72, S59, 10.1212/WNL.0b013e318199068b Olanow, 2004, Levodopa in the treatment of Parkinson's disease: current controversies, Mov. Disord, 19, 997, 10.1002/mds.20243 Olanow, 2008, A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson's disease (the ADAGIO study): rationale, design, and baseline characteristics, Mov. Disord, 23, 2194, 10.1002/mds.22218 Olanow, 2008, Why have we failed to achieve neuroprotection in Parkinson's disease?, Ann. Neurol., 64, S101 Olanow, 2003, Neuroprotection for Parkinson's disease: prospects and promises, Ann. Neurol., 53, S1, 10.1002/ana.10566 Orimo, 2005, Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease, Acta Neuropathol., 109, 583, 10.1007/s00401-005-0995-7 Pacelli, 1812, Mitochondrial defect and PGC-1alpha dysfunction in parkin-associated familial Parkinson's disease, Biochim. Biophys. Acta, 1041-1053, 2011 Palacios, 2012, Caffeine and risk of Parkinson's disease in a large cohort of men and women, Mov. Disord, 27, 1276, 10.1002/mds.25076 Palhagen, 2006, Selegiline slows the progression of the symptoms of Parkinson disease, Neurology, 66, 1200, 10.1212/01.wnl.0000204007.46190.54 Pan-Montojo, 2010, Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice, PLoS One, 5, e8762, 10.1371/journal.pone.0008762 Parkinson Study Group, 2000, A randomized controlled trial comparing pramipexole with levodopa in early Parkinson's disease: design and methods of the CALM-PD Study, Clin. Neuropharmacol, 23, 34, 10.1097/00002826-200001000-00007 Parkinson Study Group, 2002, A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study, Arch. Neurol, 59, 1937, 10.1001/archneur.59.12.1937 Parkinson Study Group, 1996, Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP subjects not requiring levodopa, Ann. Neurol, 39, 29, 10.1002/ana.410390106 Parkkinen, 2011, Does levodopa accelerate the pathologic process in Parkinson disease brain?, Neurology, 77, 1420, 10.1212/WNL.0b013e318232ab4c Popat, 2005, Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease, Neurology, 65, 383, 10.1212/01.wnl.0000171344.87802.94 Quik, 2009, Multiple roles for nicotine in Parkinson's disease, Biochem. Pharmacol., 78, 677, 10.1016/j.bcp.2009.05.003 Ragonese, 2004, Risk of Parkinson disease in women: effect of reproductive characteristics, Neurology, 62, 2010, 10.1212/WNL.62.11.2010 Ramsay, 1986, 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, 10.1016/S0006-291X(86)80483-1 Rentzos, 2007, Circulating interleukin-15 and RANTES chemokine in Parkinson's disease, Acta Neurol. Scand., 116, 374, 10.1111/j.1600-0404.2007.00894.x Riederer, 1989, Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains, J. Neurochem., 52, 515, 10.1111/j.1471-4159.1989.tb09150.x Rousseaux, 2012, Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease, Proc. Natl. Acad. Sci. USA, 109, 15918, 10.1073/pnas.1205102109 Savica, 2012, High school football and risk of neurodegeneration: a community-based study, Mayo Clin. Proc., 87, 335, 10.1016/j.mayocp.2011.12.016 Schapira, 2008, Mitochondria in the aetiology and pathogenesis of Parkinson's disease, Lancet Neurol, 7, 97, 10.1016/S1474-4422(07)70327-7 Schapira, 2011, Mitochondrial pathology in Parkinson's disease, Mt. Sinai J. Med., 78, 872, 10.1002/msj.20303 Schapira, 2010, Rationale for delayed-start study of pramipexole in Parkinson's disease: the PROUD study, Mov. Disord, 25, 1627, 10.1002/mds.23143 Schapira, 1990, Mitochondrial complex I deficiency in Parkinson's disease, J. Neurochem., 54, 823, 10.1111/j.1471-4159.1990.tb02325.x Schapira, 2011, Etiology and pathogenesis of Parkinson's disease, Mov. Disord, 26, 1049, 10.1002/mds.23732 Schapira, 2004, Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions, JAMA, 291, 358, 10.1001/jama.291.3.358 Schrag, 2000, Cross sectional prevalence survey of idiopathic Parkinson's disease and parkinsonism in London, Br. Med. J, 321, 21, 10.1136/bmj.321.7252.21 Shashidharan, 2000, TorsinA accumulation in Lewy bodies in sporadic Parkinson's disease, Brain Res., 877, 379, 10.1016/S0006-8993(00)02702-5 Shin, 2011, PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease, Cell, 144, 689, 10.1016/j.cell.2011.02.010 Sian, 1994, Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia, Ann. Neurol., 36, 348, 10.1002/ana.410360305 Solesio, 2012, Characterization of mitophagy in the 6-hydoxydopamine Parkinson's disease model, Toxicol. Sci., 129, 411, 10.1093/toxsci/kfs218 Spillantini, 1998, alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies, Proc. Natl. Acad. Sci. USA, 95, 6469, 10.1073/pnas.95.11.6469 Spina, 1989, Dopamine turnover and glutathione oxidation: implications for Parkinson disease, Proc. Natl. Acad. Sci. USA, 86, 1398, 10.1073/pnas.86.4.1398 Steigerwald, 2008, Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state, J. Neurophysiol., 100, 2515, 10.1152/jn.90574.2008 Stern, 2012, Toward a redefinition of Parkinson's disease, Mov. Disord, 27, 54, 10.1002/mds.24051 Stocchi, 2003, Neuroprotection in Parkinson's disease: clinical trials, Ann. Neurol., 53, S87, 10.1002/ana.10488 Stypula, 1996, Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with Parkinson's disease, Neuroimmunomodulation, 3, 131, 10.1159/000097237 Surmeier, 2007, Calcium, ageing, and neuronal vulnerability in Parkinson's disease, Lancet Neurol., 6, 933, 10.1016/S1474-4422(07)70246-6 Tagliati, 2010, Lack of motor symptoms progression in Parkinson's disease patients with long-term bilateral subthalamic deep brain stimulation, Int. J. Neurosci, 120, 717, 10.3109/00207454.2010.518777 Tanner, 2010, Advances in environmental epidemiology, Mov. Disord, 25, S58, 10.1002/mds.22721 Tanner, 2011, Rotenone, paraquat, and Parkinson's disease, Environ. Health Perspect., 119, 866, 10.1289/ehp.1002839 Tanner, 2009, Occupation and risk of parkinsonism: a multicenter case–control study, Arch. Neurol., 66, 1106, 10.1001/archneurol.2009.195 Tofaris, 2001, alpha-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome, FEBS Lett., 509, 22, 10.1016/S0014-5793(01)03115-5 Tofaris, 2005, Alpha-synuclein dysfunction in Lewy body diseases, Mov. Disord, 20, S37, 10.1002/mds.20538 Turski, 1991, Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists, Nature, 349, 414, 10.1038/349414a0 Usenovic, 2012, Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity, J. Neurosci., 32, 4240, 10.1523/JNEUROSCI.5575-11.2012 Vekrellis, 2012, Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson's disease and other synucleinopathies, Expert Opin. Ther. Targets, 16, 421, 10.1517/14728222.2012.674111 Velayati, 2010, The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders, Curr. Neurol. Neurosci. Rep., 10, 190, 10.1007/s11910-010-0102-x Vernon, 2007, Subtype selective antagonism of substantia nigra pars compacta Group I metabotropic glutamate receptors protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo, J. Neurochem., 103, 1075, 10.1111/j.1471-4159.2007.04860.x Vernon, 2007, Selective activation of group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutryic acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo, J. Pharmacol. Exp. Ther., 320, 397, 10.1124/jpet.106.108159 Wakabayashi, 1988, Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses, Acta Neuropathol., 76, 217, 10.1007/BF00687767 Wang, 2012, Mice overexpressing wild-type human alpha-synuclein display alterations in colonic myenteric ganglia and defecation, Neurogastroenterol. Motil., 24, e425, 10.1111/j.1365-2982.2012.01974.x Whone, 2003, Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study, Ann. Neurol., 54, 93, 10.1002/ana.10609 Witt, 2009, Biopsies of olfactory epithelium in patients with Parkinson's disease, Mov. Disord, 24, 906, 10.1002/mds.22464 Xie, 2010, Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease, J. Neurochem., 115, 188, 10.1111/j.1471-4159.2010.06914.x Xu, 2011, Accumulation and distribution of alpha-synuclein and ubiquitin in the CNS of Gaucher disease mouse models, Mol. Genet. Metab., 102, 436, 10.1016/j.ymgme.2010.12.014 Yong, 1986, Monoamine oxidase B, smoking, and Parkinson's disease, J. Neurol. Sci., 72, 265, 10.1016/0022-510X(86)90014-6 Yue, 2011, Genetic LRRK2 models of Parkinson's disease: dissecting the pathogenic pathway and exploring clinical applications, Mov. Disord, 26, 1386, 10.1002/mds.23737 Zeng, 2005, Proteasomal activity in brain differs between species and brain regions and changes with age, Mech. Ageing Dev., 126, 760, 10.1016/j.mad.2005.01.008 Zheng, 2010, PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease, Sci. Transl. Med., 2, 10.1126/scitranslmed.3001059 Zigmond, 2009, Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency, Parkinsonism Relat. Disord., 15, S42, 10.1016/S1353-8020(09)70778-3