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The two-century journey of Parkinson disease research

Abstract

Since the first formal description of Parkinson disease (PD) two centuries ago, our understanding of this common neurodegenerative disorder has expanded at all levels of description, from the delineation of its clinical phenotype to the identification of its neuropathological features, neurochemical processes and genetic factors. Along the way, findings have led to novel hypotheses about how the disease develops and progresses, challenging our understanding of how neurodegenerative disorders wreak havoc on human health. In this Timeline article, I recount the fascinating 200-year journey of PD research.

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Figure 1: The 200 years of Parkinson disease research.
Figure 2: Direct and indirect pathways of the basal ganglia motor circuits in health and parkinsonism.
Figure 3: Potential pathogenic mechanisms involved in Parkinson disease.

References

  1. 1

    Parkinson, J. An Essay on the Shaking Palsy (Whittingham and Rowland, 1817).

    Google Scholar 

  2. 2

    Goetz, C. G. The history of Parkinson's disease: early clinical descriptions and neurological therapies. Cold Spring Harb. Perspect. Med. 1, a008862 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Charcot, J. M. in Oeuvres Complètes (Tome 1). Leçons sur les Maladies du Système Nerveux (eds Delahaye, A. & Lecrosnier, E.) 155–188 (in French) (Bureaux du Progrès Médical, 1872).

    Google Scholar 

  4. 4

    Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).

    CAS  PubMed  Google Scholar 

  5. 5

    Casals, J., Elizan, T. S. & Yahr, M. D. Postencephalitic parkinsonism — a review. J. Neural Transm. (Vienna) 105, 645–676 (1998).

    CAS  Google Scholar 

  6. 6

    Economo, C. V. Encephalitis Lethargica: its Sequelae and Treatment (Oxford Univ. Press, 1931).

    Google Scholar 

  7. 7

    Kalia, L. V. & Lang, A. E. Parkinson's disease. Lancet 386, 896–912 (2015).

    CAS  PubMed  Google Scholar 

  8. 8

    Postuma, R. B. & Berg, D. Advances in markers of prodromal Parkinson disease. Nat. Rev. Neurol. 12, 622–634 (2016).

    CAS  Google Scholar 

  9. 9

    Blocq, C. & Marinescu, G. Sur un cas de tremblement parkinsonien hémiplégique symptomatique d'une tumeur du pédoncule cérébral. C. R. Cos. Biol. 45, 105–111 (in French) (1893).

    Google Scholar 

  10. 10

    Brissaud, E. Leçons sur les Maladies Nerveuses Vol. 2 (in French) (Masson, 1899).

    Google Scholar 

  11. 11

    Trétiakoff, C. Contribution à l'étude de l'anatomie pathologique du locus niger de Soemmering avec quelques deductions relatives a la pathogenie des troubles du tonus musculaire et de la maladie de Parkinson (in French) (Université de Paris, 1919).

    Google Scholar 

  12. 12

    Marsden, C. D. Neuromelanin and Parkinson's disease. J. Neural Transm. Suppl. 19, 121–141 (1983).

    CAS  PubMed  Google Scholar 

  13. 13

    Lewy, F. Zur pathologischen Anatomie der Paralysis agitans. Dtsch. Z. Nervenheilk 50, 50–55 (in German) (1913).

    Google Scholar 

  14. 14

    Shults, C. W. Lewy bodies. Proc. Natl Acad. Sci. USA 103, 1661–1668 (2006).

    CAS  PubMed  Google Scholar 

  15. 15

    Wilson, S. A. K. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 34, 295–509 (1912).

    Google Scholar 

  16. 16

    Anden, N. E., Dahlstroem, A., Fuxe, K. & Larsson, K. Further evidence for the presence of nigro-neostriatal dopamine neurons in the rat. Am. J. Anat. 116, 329–333 (1965).

    CAS  PubMed  Google Scholar 

  17. 17

    Anden, N. E. et al. Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci. 3, 523–530 (1964).

    CAS  Google Scholar 

  18. 18

    Poirier, L. J. & Sourkes, T. L. Influence of the substantia nigra on the catecholamine content of the striatum. Brain 88, 181–192 (1965).

    CAS  PubMed  Google Scholar 

  19. 19

    Goldstein, M., Anagnoste, B., Owen, W. S. & Battista, A. F. The effects of ventromedial tegmental lesions on the biosynthesis of catecholamines in the striatum. Life Sci. 5, 2171–2176 (1966).

    CAS  Google Scholar 

  20. 20

    Dahlström, A. & Fuxe, K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Scand. Suppl. 232, 1–55 (1964).

    Google Scholar 

  21. 21

    Hassler, R. Zur Pathologie der Paralysis agitans und des postenzephalitischen Parkinsonismus. J. Psychol. Neurol. 48, 387–476 (in German) (1938).

    Google Scholar 

  22. 22

    Greenfield, J. G. & Bosanquet, F. D. The brain-stem lesions in Parkinsonism. J. Neurol. Neurosurg. Psychiatry 16, 213–226 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Hirsch, E., Graybiel, A. M. & Agid, Y. A. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334, 345–348 (1988).

    CAS  PubMed  Google Scholar 

  24. 24

    Fahn, S. & Cohen, G. The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann. Neurol. 32, 804–812 (1992).

    CAS  PubMed  Google Scholar 

  25. 25

    Fearnley, J. M. & Lees, A. J. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114, 2283–2301 (1991).

    Google Scholar 

  26. 26

    Braak, H. et al. Nigral and extranigral pathology in Parkinson's disease. J. Neural Transm. Suppl. 46, 15–31 (1995).

    CAS  PubMed  Google Scholar 

  27. 27

    Montagu, K. A. Catechol compounds in rat tissues and in brains of different animals. Nature 180, 244–245 (1957).

    CAS  PubMed  Google Scholar 

  28. 28

    Carlsson, A., Lindquist, M., Magnusson, T. & Waldeck, B. On the presence of 3-hydroxytyramine in brain. Science 127, 471–471 (1958).

    CAS  PubMed  Google Scholar 

  29. 29

    Bertler, A. & Rosengren, E. Occurrence and distribution of dopamine in brain and other tissues. Experientia 15, 10–11 (1959).

    CAS  PubMed  Google Scholar 

  30. 30

    Sano, I. et al. Distribution of catechol compounds in human brain. Biochim. Biophys. Acta 32, 586–587 (1959).

    CAS  PubMed  Google Scholar 

  31. 31

    Carlsson, A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol. Rev. 11, 490–493 (1959).

    CAS  PubMed  Google Scholar 

  32. 32

    Carlsson, A., Lindqvist, M. & Magnusson, T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180, 1200 (1957).

    CAS  Google Scholar 

  33. 33

    Sano, I. Biochemistry of the extrapyramidal system. Shinkei Kennkyu No Shinpo 5, 42–48 (in Japanese) (1960).

    Google Scholar 

  34. 34

    Ehringer, H. & Hornykiewicz, O. Verteilung von noradrenalin und dopamin (3-hydroxytyramin) im gehirn des menschen und ihr verhalten bei erkrankungen des extrapyramidalen systems. Klin. Wochenschr. 38, 1236–1239 (in German) (1960).

    CAS  PubMed  Google Scholar 

  35. 35

    Fahn, S. The medical treatment of Parkinson disease from James Parkinson to George Cotzias. Mov. Disord. 30, 4–18 (2015).

    CAS  PubMed  Google Scholar 

  36. 36

    Olanow, C. W., Obeso, J. A. & Stocchi, F. Drug insight: continuous dopaminergic stimulation in the treatment of Parkinson's disease. Nat. Clin. Pract. Neurol. 2, 382–392 (2006).

    CAS  PubMed  Google Scholar 

  37. 37

    Smith, Y., Wichmann, T., Factor, S. A. & DeLong, M. R. Parkinson's disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharmacology 37, 213–246 (2012).

    CAS  PubMed  Google Scholar 

  38. 38

    Missale, C., Nash, S. R., Robinson, S. W., Jaber, M. & Caron, M. G. Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225 (1998).

    CAS  PubMed  Google Scholar 

  39. 39

    Hokfelt, T. & Ungerstedt, U. Specificity of 6-hydroxydopamine induced degeneration of central monoamine neurones: an electron and fluorescence microscopic study with special reference to intracerebral injection on the nigro-striatal dopamine system. Brain Res. 60, 269–297 (1973).

    CAS  PubMed  Google Scholar 

  40. 40

    Ungerstedt, U. & Arbuthnott, G. Quantitative recording of rotational behaviour in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res. 24, 485–493 (1970).

    CAS  PubMed  Google Scholar 

  41. 41

    Barker, R. A., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease-past insights and future potential. Nat. Rev. Neurol. 11, 492–503 (2015).

    CAS  Google Scholar 

  42. 42

    Meyers, R. The modification of alternating tremors, rigidity and festination by surgery of the basal ganglia. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 21, 602–665 (1942).

    Google Scholar 

  43. 43

    Bergman, H., Wichmann, T. & DeLong, M. R. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249, 1436–1438 (1990).

    CAS  PubMed  Google Scholar 

  44. 44

    Hammond, C., Bergman, H. & Brown, P. Pathological synchronization in Parkinson's disease: networks, models and treatments. Trends Neurosci. 30, 357–364 (2007).

    CAS  PubMed  Google Scholar 

  45. 45

    de Hemptinne, C. et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease. Nat. Neurosci. 18, 779–786 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Rosin, B. et al. Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron 72, 370–384 (2011).

    CAS  PubMed  Google Scholar 

  47. 47

    Niethammer, M., Feigin, A. & Eidelberg, D. Functional neuroimaging in Parkinson's disease. Cold Spring Harb. Perspect. Med. 2, a009274 (2012).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Gingrich, J. A. & Caron, M. G. Recent advances in the molecular biology of dopamine receptors. Annu. Rev. Neurosci. 16, 299–321 (1993).

    CAS  PubMed  Google Scholar 

  49. 49

    Walaas, S. I., Aswad, D. W. & Greengard, P. A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. Nature 301, 69–71 (1983).

    CAS  Google Scholar 

  50. 50

    DeLong, M. R. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13, 281–285 (1990).

    CAS  Google Scholar 

  51. 51

    Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989).

    CAS  PubMed  Google Scholar 

  52. 52

    Crossman, A. R. Neural mechanisms in disorders of movement. Comp. Biochem. Physiol. A Comp. Physiol. 93, 141–149 (1989).

    CAS  PubMed  Google Scholar 

  53. 53

    Gerfen, C. R. et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250, 1429–1432 (1990).

    CAS  Google Scholar 

  54. 54

    Kravitz, A. V. et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Mink, J. W. in Fundamental Neuroscience Ch. 30 (eds Squire, L. R. et al.) 653–676 (Academic Press, 2013).

    Google Scholar 

  56. 56

    Jin, X., Tecuapetla, F. & Costa, R. M. Basal ganglia subcircuits distinctively encode the parsing and concatenation of action sequences. Nat. Neurosci. 17, 423–430 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Tecuapetla, F., Jin, X., Lima, S. Q. & Costa, R. M. Complementary contributions of striatal projection pathways to action initiation and execution. Cell 166, 703–715 (2016).

    CAS  Google Scholar 

  58. 58

    Panigrahi, B. et al. Dopamine is required for the neural representation and control of movement vigor. Cell 162, 1418–1430 (2015).

    CAS  PubMed  Google Scholar 

  59. 59

    Yttri, E. A. & Dudman, J. T. Opponent and bidirectional control of movement velocity in the basal ganglia. Nature 533, 402–406 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Mazzoni, P., Hristova, A. & Krakauer, J. W. Why don't we move faster? Parkinson's disease, movement vigor, and implicit motivation. J. Neurosci. 27, 7105–7116 (2007).

    CAS  PubMed  Google Scholar 

  61. 61

    Langston, J. W., Ballard, P. & Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983).

    CAS  Google Scholar 

  62. 62

    Davis, G. C. et al. Chronic parkinsonism secondary to intravenous-injection of meperidine analogs. Psychiatry Res. 1, 249–254 (1979).

    CAS  Google Scholar 

  63. 63

    Schapira, A. H. et al. Mitochondrial complex I deficiency in Parkinson's disease. J. Neurochem. 54, 823–827 (1990).

    CAS  PubMed  Google Scholar 

  64. 64

    Schapira, A. H. et al. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson's disease. J. Neurochem. 55, 2142–2145 (1990).

    CAS  PubMed  Google Scholar 

  65. 65

    Schon, E. A. & Przedborski, S. Mitochondria: the next (neurode)generation. Neuron 70, 1033–1053 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Nishioka, K. et al. Genetic variation of the mitochondrial complex I subunit NDUFV2 and Parkinson's disease. Parkinsonism Relat. Disord. 16, 686–687 (2010).

    PubMed  PubMed Central  Google Scholar 

  67. 67

    Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518–520 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515–517 (2006).

    CAS  Google Scholar 

  69. 69

    Kosel, S. et al. Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease. Neurogenetics 1, 197–204 (1998).

    CAS  PubMed  Google Scholar 

  70. 70

    van der Walt, J. M. et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am. J. Hum. Genet. 72, 804–811 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Wooten, G. F. et al. Maternal inheritance in Parkinson's disease. Ann. Neurol. 41, 265–268 (1997).

    CAS  PubMed  Google Scholar 

  72. 72

    Swerdlow, R. H. et al. Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson's disease family. Ann. Neurol. 44, 873–881 (1998).

    CAS  PubMed  Google Scholar 

  73. 73

    Shoffner, J. M., Brown, M. & Huoponen, K. A mitochondrial DNA (mtDNA) mutation associated with maternally inherited deafness and Parkinson's disease (PD). Neurology 46, (2 Suppl.) A331 (1996).

    Google Scholar 

  74. 74

    Thyagarajan, D. et al. A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann. Neurol. 48, 730–736 (2000).

    CAS  PubMed  Google Scholar 

  75. 75

    Luoma, P. et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364, 875–882 (2004).

    CAS  PubMed  Google Scholar 

  76. 76

    Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    CAS  Google Scholar 

  77. 77

    Mizuno, Y., Hattori, N., Mori, H., Suzuki, T. & Tanaka, K. Parkin and Parkinson's disease. Curr. Opin. Neurol. 14, 477–482 (2001).

    CAS  PubMed  Google Scholar 

  78. 78

    Goldberg, M. S. et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278, 43628–43635 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    Palacino, J. J. et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279, 18614–18622 (2004).

    CAS  PubMed  Google Scholar 

  80. 80

    Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003).

    CAS  PubMed  Google Scholar 

  81. 81

    Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302–305 (2000).

    CAS  PubMed  Google Scholar 

  82. 82

    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  Google Scholar 

  83. 83

    Shin, J. H. et al. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 144, 689–702 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Austin, S. & St-Pierre, J. PGC1alpha and mitochondrial metabolism — emerging concepts and relevance in ageing and neurodegenerative disorders. J. Cell Sci. 125, 4963–4971 (2012).

    CAS  PubMed  Google Scholar 

  85. 85

    Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).

    CAS  Google Scholar 

  86. 86

    Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).

    CAS  Google Scholar 

  87. 87

    Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Valente, E. M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    CAS  Google Scholar 

  89. 89

    Clark, I. E. et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162–1166 (2006).

    CAS  Google Scholar 

  90. 90

    Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157–1161 (2006).

    CAS  Google Scholar 

  91. 91

    Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Burchell, V. S. et al. The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat. Neurosci. 16, 1257–1265 (2013).

    CAS  PubMed  Google Scholar 

  93. 93

    Lesage, S. et al. Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy. Am. J. Hum. Genet. 98, 500–513 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  Google Scholar 

  95. 95

    Kruger, R. et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat. Genet. 18, 106–108 (1998).

    CAS  PubMed  Google Scholar 

  96. 96

    Zarranz, J. J. et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173 (2004).

    CAS  PubMed  Google Scholar 

  97. 97

    Lesage, S. et al. G51D alpha-synuclein mutation causes a novel Parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459–471 (2013).

    CAS  PubMed  Google Scholar 

  98. 98

    Proukakis, C. et al. A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80, 1062–1064 (2013).

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    CAS  Google Scholar 

  100. 100

    Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14, 38–48 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Munoz, E. et al. Identification of Spanish familial Parkinson's disease and screening for the Ala53Thr mutation of the alpha-synuclein gene in early onset patients. Neurosci. Lett. 235, 57–60 (1997).

    CAS  PubMed  Google Scholar 

  102. 102

    Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998).

    CAS  PubMed  Google Scholar 

  103. 103

    Singleton, A. B. et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    CAS  Google Scholar 

  104. 104

    Chartier-Harlin, M. C. et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).

    CAS  PubMed  Google Scholar 

  105. 105

    Ibanez, P. et al. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169–1171 (2004).

    CAS  PubMed  Google Scholar 

  106. 106

    Gowers, W. R. (ed) A Manual of Diseases of the Nervous System 2nd edn (Blakiston, 1888).

    Google Scholar 

  107. 107

    Marder, K. et al. Risk of Parkinson's disease among first-degree relatives: a community-based study. Neurology 47, 155–160 (1996).

    CAS  PubMed  Google Scholar 

  108. 108

    Chen, K.-M. & Chase, T. N. in Handbook of Clinical Neurology. Extrapyramidal disorders Vol. 49 (eds Vinken, P. J., Bruyn, G. W. & Klawans, H. L.) 167–183 (Elsevier, 1986).

    Google Scholar 

  109. 109

    Tanner, C., Goldman, S. M. & Ross, G. W. in Parkinson's Disease and Movement Disorders Ch. 7 (eds Jankovic, J. & Tolosa, E.) 90–103 (Lippincott Williams & Wilkins, 2002).

    Google Scholar 

  110. 110

    Hernan, M. A., Takkouche, B., Caamano-Isorna, F. & Gestal-Otero, J. J. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann. Neurol. 52, 276–284 (2002).

    PubMed  Google Scholar 

  111. 111

    Thiruchelvam, M., Brockel, B. J., Richfield, E. K., Baggs, R. B. & Cory-Slechta, D. A. Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease? Brain Res. 873, 225–234 (2000).

    CAS  PubMed  Google Scholar 

  112. 112

    Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301–1306 (2000).

    CAS  PubMed  Google Scholar 

  113. 113

    Trinh, J. & Farrer, M. Advances in the genetics of Parkinson disease. Nat. Rev. Neurol. 9, 445–454 (2013).

    CAS  PubMed  Google Scholar 

  114. 114

    Lucking, C. B. et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N. Engl. J. Med. 342, 1560–1567 (2000).

    CAS  PubMed  Google Scholar 

  115. 115

    Gilks, W. P. et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415–416 (2005).

    CAS  PubMed  Google Scholar 

  116. 116

    Martin, E. R. et al. Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA 286, 2245–2250 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Zareparsi, S. et al. Age at onset of Parkinson disease and apolipoprotein E genotypes. Am. J. Med. Genet. 107, 156–161 (2002).

    PubMed  Google Scholar 

  118. 118

    Li, Y. J. et al. Age at onset in two common neurodegenerative diseases is genetically controlled. Am. J. Hum. Genet. 70, 985–993 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Aharon-Peretz, J., Rosenbaum, H. & Gershoni-Baruch, R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972–1977 (2004).

    CAS  PubMed  Google Scholar 

  120. 120

    Heman-Ackah, S. M., Hallegger, M., Rao, M. S. & Wood, M. J. RISC in PD: the impact of microRNAs in Parkinson's disease cellular and molecular pathogenesis. Front. Mol. Neurosci. 6, 40 (2013).

    PubMed  PubMed Central  Google Scholar 

  121. 121

    Tanner, C. M. et al. Parkinson disease in twins: an etiologic study. JAMA 281, 341–346 (1999).

    CAS  PubMed  Google Scholar 

  122. 122

    Dickson, D. et al. Pathology of PD in monozygotic twins with a 20-year discordance interval. Neurology 56, 981–982 (2001).

    CAS  PubMed  Google Scholar 

  123. 123

    Keller, M. F. et al. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum. Mol. Genet. 21, 4996–5009 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Wood, A. R. et al. Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation. PLoS ONE 8, e64343 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat. Genet. 46, 989–993 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004).

    CAS  PubMed  Google Scholar 

  127. 127

    Peelaerts, W. et al. Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).

    CAS  Google Scholar 

  128. 128

    Przedborski, S. in Handbook of Clinical Neurology. Parkinson's Disease and Related Disoders Ch. 26 (eds Koller, W. C. & Melamed, E.) 535–551 (Elsevier, 2007).

    Google Scholar 

  129. 129

    McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285–1291 (1988).

    CAS  PubMed  Google Scholar 

  130. 130

    Forno, L. S., DeLanney, L. E., Irwin, I., Di Monte, D. & Langston, J. W. Astrocytes and Parkinson's disease. Prog. Brain Res. 94, 429–436 (1992).

    CAS  PubMed  Google Scholar 

  131. 131

    Banati, R. B., Daniel, S. E. & Blunt, S. B. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov. Disord. 13, 221–227 (1998).

    CAS  PubMed  Google Scholar 

  132. 132

    Mirza, B., Hadberg, H., Thomsen, P. & Moos, T. The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. Neuroscience 95, 425–432 (2000).

    CAS  PubMed  Google Scholar 

  133. 133

    Valera, E., Spencer, B. & Masliah, E. Immunotherapeutic approaches targeting amyloid-beta, alpha-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics 13, 179–189 (2016).

    CAS  PubMed  Google Scholar 

  134. 134

    Walsh, D. M. & Selkoe, D. J. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat. Rev. Neurosci. 17, 251–260 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Google Scholar 

  136. 136

    Mao, X. et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Volpicelli-Daley, L. A. et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Sharon, G., Sampson, T. R., Geschwind, D. H. & Mazmanian, S. K. The central nervous system and the gut microbiome. Cell 167, 915–932 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author is supported by the US National Institutes of Health (NIH)/NIDS awards NS099862 and NS072428, DOD Award 13-1-0416 and from Target-ALS and the Project-ALS.

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Correspondence to Serge Przedborski.

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Przedborski, S. The two-century journey of Parkinson disease research. Nat Rev Neurosci 18, 251–259 (2017). https://doi.org/10.1038/nrn.2017.25

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