1932

Abstract

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathmechdis-031521-034145
2023-01-24
2024-06-24
Loading full text...

Full text loading...

/deliver/fulltext/pathol/18/1/annurev-pathmechdis-031521-034145.html?itemId=/content/journals/10.1146/annurev-pathmechdis-031521-034145&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Titova N, Padmakumar C, Lewis SJG, Chaudhuri KR. 2017. Parkinson's: a syndrome rather than a disease?. J. Neural Transm. 124:8907–14
    [Google Scholar]
  2. 2.
    Weiner WJ. 2008. There is no Parkinson disease. Arch. Neurol. 65:6705–8
    [Google Scholar]
  3. 3.
    Bloem BR, Okun MS, Klein C. 2021. Parkinson's disease. Lancet 397:102912284–303
    [Google Scholar]
  4. 4.
    Dorsey ER, Sherer T, Okun MS, Bloemd BR. 2018. The emerging evidence of the Parkinson pandemic. J. Parkinsons Dis. 8:s1S3–8
    [Google Scholar]
  5. 5.
    Berg D, Borghammer P, Fereshtehnejad SM, Heinzel S, Horsager J et al. 2021. Prodromal Parkinson disease subtypes—key to understanding heterogeneity. Nat. Rev. Neurol. 17:6349–61
    [Google Scholar]
  6. 6.
    Armstrong MJ, Okun MS. 2020. Diagnosis and treatment of Parkinson disease: a review. JAMA 323:6548–60
    [Google Scholar]
  7. 7.
    Tolosa E, Garrido A, Scholz SW, Poewe W. 2021. Challenges in the diagnosis of Parkinson's disease. Lancet Neurol. 20:5385–97
    [Google Scholar]
  8. 8.
    Mestre TA, Fereshtehnejad SM, Berg D, Bohnen NI, Dujardin K et al. 2021. Parkinson's disease subtypes: critical appraisal and recommendations. J. Parkinsons Dis. 11:2395–404
    [Google Scholar]
  9. 9.
    Schapira AHV, Chaudhuri KR, Jenner P. 2017. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 18:7435–50
    [Google Scholar]
  10. 10.
    Fereshtehnejad SM, Yao C, Pelletier A, Montplaisir JY, Gagnon JF, Postuma RB. 2019. Evolution of prodromal Parkinson's disease and dementia with Lewy bodies: a prospective study. Brain 142:72051–67
    [Google Scholar]
  11. 11.
    Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F et al. 2013. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12:5443–53
    [Google Scholar]
  12. 12.
    Hely MA, Reid WGJ, Adena MA, Halliday GM, Morris JGL. 2008. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov. Disord. 23:6837–44
    [Google Scholar]
  13. 13.
    Walker Z, Possin KL, Boeve BF, Aarsland D. 2015. Lewy body dementias. Lancet 386:100041683–97
    [Google Scholar]
  14. 14.
    Weintraub D, Aarsland D, Chaudhuri KR, Dobkin RD, Leentjens AF et al. 2022. The neuropsychiatry of Parkinson's disease: advances and challenges. Lancet Neurol. 21:189–102
    [Google Scholar]
  15. 15.
    Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. 2017. Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression. Brain 140:71959–76
    [Google Scholar]
  16. 16.
    Rizzo G, Copetti M, Arcuti S, Martino D, Fontana A, Logroscino G. 2016. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology 86:6566–76
    [Google Scholar]
  17. 17.
    Stamelou M, Respondek G, Giagkou N, Whitwell JL, Kovacs GG, Höglinger GU. 2021. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat. Rev. Neurol. 17:10601–20
    [Google Scholar]
  18. 18.
    Fanciulli A, Wenning GK. 2015. Multiple-system atrophy. N. Engl. J. Med. 372:3249–63
    [Google Scholar]
  19. 19.
    McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor J-P et al. 2017. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89:188–100
    [Google Scholar]
  20. 20.
    Bergman H, Wichmann T, DeLong MR. 1990. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249:49751436–38
    [Google Scholar]
  21. 21.
    Kravitz AV, Freeze BS, Parker PRL, Kay K, Thwin MT et al. 2010. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466:7306622–26
    [Google Scholar]
  22. 22.
    Parker JG, Marshall JD, Ahanonu B, Wu Y-W, Kim TH et al. 2018. Diametric neural ensemble dynamics in parkinsonian and dyskinetic states. Nature 557:7704177–82
    [Google Scholar]
  23. 23.
    O'Keeffe GW, Sullivan AM 2018. Evidence for dopaminergic axonal degeneration as an early pathological process in Parkinson's disease. Parkinsonism Relat. Disord. 56:9–15
    [Google Scholar]
  24. 24.
    Fearnley JM, Lees AJ. 1991. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114:Part 52283–301
    [Google Scholar]
  25. 25.
    Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG et al. 2013. Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain 136:82419–31
    [Google Scholar]
  26. 26.
    Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24:2197–211
    [Google Scholar]
  27. 27.
    Surmeier DJ, Obeso JA, Halliday GM. 2017. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18:2101–13
    [Google Scholar]
  28. 28.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. 1997. Alpha-synuclein in Lewy bodies. Nature 388:6645839–40
    [Google Scholar]
  29. 29.
    Dugger BN, Dickson DW. 2017. Pathology of neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 9:7a028035
    [Google Scholar]
  30. 30.
    Burré J, Sharma M, Südhof TC. 2018. Cell biology and pathophysiology of α-synuclein. Cold Spring Harb. Perspect. Med. 8:3a024091
    [Google Scholar]
  31. 31.
    Shahmoradian SH, Lewis AJ, Genoud C, Hench J, Moors TE et al. 2019. Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 22:71099–109
    [Google Scholar]
  32. 32.
    Kayed R, Dettmer U, Lesné SE. 2020. Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: expression, spreading, and cross-talk. J. Parkinsons Dis. 10:3791–818
    [Google Scholar]
  33. 33.
    Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P et al. 2012. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:6109949–53
    [Google Scholar]
  34. 34.
    Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A et al. 2018. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557:7706558–63
    [Google Scholar]
  35. 35.
    Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P et al. 2020. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature 578:7794273–77
    [Google Scholar]
  36. 36.
    Peng C, Trojanowski JQ, Lee VM-Y. 2020. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16:4199–212
    [Google Scholar]
  37. 37.
    Kosaka K, Tsuchiya K, Yoshimura M. 1988. Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin. Neuropathol. 7:6299–305
    [Google Scholar]
  38. 38.
    Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J et al. 2009. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 117:6613–34
    [Google Scholar]
  39. 39.
    Tsukita K, Sakamaki-Tsukita H, Tanaka K, Suenaga T, Takahashi R. 2019. Value of in vivo α-synuclein deposits in Parkinson's disease: a systematic review and meta-analysis. Mov. Disord. 34:101452–63
    [Google Scholar]
  40. 40.
    Chahine LM, Beach TG, Brumm MC, Adler CH, Coffey CS et al. 2020. In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease. Neurology 95:9e1267–84
    [Google Scholar]
  41. 41.
    Kim S, Kwon S-H, Kam T-I, Panicker N, Karuppagounder SS et al. 2019. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson's disease. Neuron 103:4627–41.e7
    [Google Scholar]
  42. 42.
    Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L et al. 2015. Vagotomy and subsequent risk of Parkinson's disease. Ann. Neurol. 78:4522–29
    [Google Scholar]
  43. 43.
    Jellinger KA. 2019. Is Braak staging valid for all types of Parkinson's disease?. J. Neural Transm. 126:4423–31
    [Google Scholar]
  44. 44.
    Halliday G, Hely M, Reid W, Morris J 2008. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol. 115:4409–15
    [Google Scholar]
  45. 45.
    Adler CH, Beach TG, Zhang N, Shill HA, Driver-Dunckley E et al. 2019. Unified staging system for Lewy body disorders: clinicopathologic correlations and comparison to Braak staging. J. Neuropathol. Exp. Neurol. 78:10891–99
    [Google Scholar]
  46. 46.
    Raunio A, Kaivola K, Tuimala J, Kero M, Oinas M et al. 2019. Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85. Acta Neuropathol. 138:5771–82
    [Google Scholar]
  47. 47.
    Horsager J, Andersen KB, Knudsen K, Skjærbæk C, Fedorova TD et al. 2020. Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study. Brain 143:103077–88
    [Google Scholar]
  48. 48.
    Milber JM, Noorigian JV, Morley JF, Petrovitch H, White L et al. 2012. Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 79:242307–14
    [Google Scholar]
  49. 49.
    Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ, Rozemuller AJM, van de Berg WDJ. 2014. Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease. Mov. Disord. 29:101244–51
    [Google Scholar]
  50. 50.
    Dugger BN, Adler CH, Shill HA, Caviness J, Jacobson S et al. 2014. Concomitant pathologies among a spectrum of parkinsonian disorders. Parkinsonism Relat. Disord. 20:5525–29
    [Google Scholar]
  51. 51.
    Robinson JL, Lee EB, Xie SX, Rennert L, Suh E et al. 2018. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141:72181–93
    [Google Scholar]
  52. 52.
    Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H et al. 2007. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 114:3221–29
    [Google Scholar]
  53. 53.
    Kapasi A, DeCarli C, Schneider JA. 2017. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 134:2171–86
    [Google Scholar]
  54. 54.
    Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M et al. 2001. β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. PNAS 98:2112245–50
    [Google Scholar]
  55. 55.
    Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. 2010. Synergistic interactions between Aβ, tau, and α-synuclein: acceleration of neuropathology and cognitive decline. J. Neurosci. 30:217281–89
    [Google Scholar]
  56. 56.
    Bassil F, Brown HJ, Pattabhiraman S, Iwasyk JE, Maghames CM et al. 2020. Amyloid-beta (Aβ) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with Aβ pathology. Neuron 105:2260–75.e6
    [Google Scholar]
  57. 57.
    Buchman AS, Yu L, Wilson RS, Leurgans SE, Nag S et al. 2019. Progressive parkinsonism in older adults is related to the burden of mixed brain pathologies. Neurology 92:16e1821–30
    [Google Scholar]
  58. 58.
    Schneider SA, Alcalay RN. 2017. Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov. Disord. 32:111504–23
    [Google Scholar]
  59. 59.
    Ascherio A, Schwarzschild MA. 2016. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 15:121257–72
    [Google Scholar]
  60. 60.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A et al. 1997. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276:53212045–47
    [Google Scholar]
  61. 61.
    Blauwendraat C, Nalls MA, Singleton AB. 2020. The genetic architecture of Parkinson's disease. Lancet Neurol. 19:2170–78
    [Google Scholar]
  62. 62.
    Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G et al. 2012. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann. Neurol. 72:6893–901
    [Google Scholar]
  63. 63.
    Sellbach AN, Boyle RS, Silburn PA, Mellick GD. 2006. Parkinson's disease and family history. Parkinsonism Relat. Disord. 12:7399–409
    [Google Scholar]
  64. 64.
    Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S et al. 2019. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18:121091–102
    [Google Scholar]
  65. 65.
    Trinh J, Zeldenrust FMJ, Huang J, Kasten M, Schaake S et al. 2018. Genotype-phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review. Mov. Disord. 33:121857–70
    [Google Scholar]
  66. 66.
    Wong YC, Krainc D. 2017. α-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med. 23:21–13
    [Google Scholar]
  67. 67.
    Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J et al. 2004. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:4595–600
    [Google Scholar]
  68. 68.
    Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G et al. 2009. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361:171651–61
    [Google Scholar]
  69. 69.
    Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M et al. 2004. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:4601–7
    [Google Scholar]
  70. 70.
    Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A et al. 2008. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7:7583–90
    [Google Scholar]
  71. 71.
    Trinh J, Guella I, Farrer MJ. 2014. Disease penetrance of late-onset parkinsonism: a meta-analysis. JAMA Neurol. 71:121535–39
    [Google Scholar]
  72. 72.
    Lee AJ, Wang Y, Alcalay RN, Mejia-Santana H, Saunders-Pullman R et al. 2017. Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov. Disord. 32:101432–38
    [Google Scholar]
  73. 73.
    Kluss JH, Mamais A, Cookson MR. 2019. LRRK2 links genetic and sporadic Parkinson's disease. Biochem. Soc. Trans. 47:2651–61
    [Google Scholar]
  74. 74.
    Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L et al. 2010. Frequency of known mutations in early-onset Parkinson disease—implication for genetic counseling: the Consortium on Risk for Early Onset Parkinson Disease study. Arch. Neurol. 67:91116–22
    [Google Scholar]
  75. 75.
    Trinh J, Lohmann K, Baumann H, Balck A, Borsche M et al. 2019. Utility and implications of exome sequencing in early-onset Parkinson's disease. Mov. Disord. 34:1133–37
    [Google Scholar]
  76. 76.
    Erro R, Bhatia KP, Tinazzi M. 2015. Parkinsonism following neuroleptic exposure: a double-hit hypothesis?. Mov. Disord. 30:6780–85
    [Google Scholar]
  77. 77.
    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S et al. 2003. α-Synuclein locus triplication causes Parkinson's disease. Science 302:5646841
    [Google Scholar]
  78. 78.
    Kasten M, Hartmann C, Hampf J, Schaake S, Westenberger A et al. 2018. Genotype-phenotype relations for the Parkinson's disease genes Parkin, PINK1, DJ1: MDSGene systematic review. Mov. Disord. 33:5730–41
    [Google Scholar]
  79. 79.
    Ambroziak W, Koziorowski D, Duszyc K, Górka-Skoczylas P, Potulska-Chromik A et al. 2015. Genomic instability in the PARK2 locus is associated with Parkinson's disease. J. Appl. Genet. 56:4451–61
    [Google Scholar]
  80. 80.
    Robak LA, Du R, Yuan B, Gu S, Alfradique-Dunham I et al. 2020. Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease. Neurol. Genet. 6:5e498
    [Google Scholar]
  81. 81.
    Butcher NJ, Kiehl T-R, Hazrati L-N, Chow EWC, Rogaeva E et al. 2013. Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications. JAMA Neurol. 70:111359–66
    [Google Scholar]
  82. 82.
    Shi C-H, Fan Y, Yang J, Yuan Y-P, Shen S et al. 2021. NOTCH2NLC intermediate-length repeat expansions are associated with Parkinson disease. Ann. Neurol. 89:1182–87
    [Google Scholar]
  83. 83.
    Antenora A, Rinaldi C, Roca A, Pane C, Lieto M et al. 2017. The multiple faces of spinocerebellar ataxia type 2. Ann. Clin. Transl. Neurol. 4:9687–95
    [Google Scholar]
  84. 84.
    Wang L, Aasly JO, Annesi G, Bardien S, Bozi M et al. 2015. Large-scale assessment of polyglutamine repeat expansions in Parkinson disease. Neurology 85:151283–92
    [Google Scholar]
  85. 85.
    Lubbe SJ, Bustos BI, Hu J, Krainc D, Joseph T et al. 2021. Assessing the relationship between monoallelic PRKN mutations and Parkinson's risk. Hum. Mol. Genet. 30:178–86
    [Google Scholar]
  86. 86.
    Yu E, Rudakou U, Krohn L, Mufti K, Ruskey JA et al. 2021. Analysis of heterozygous PRKN variants and copy-number variations in Parkinson's Disease. Mov. Disord. 36:1178–87
    [Google Scholar]
  87. 87.
    Wittke C, Petkovic S, Dobricic V, Schaake S, Respondek G et al. 2021. Genotype-phenotype relations for the atypical parkinsonism genes: MDSGene systematic review. Mov. Disord. 36:71499–510
    [Google Scholar]
  88. 88.
    Ahlskog JE. 2009. Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease. Parkinsonism Relat. Disord. 15:10721–27
    [Google Scholar]
  89. 89.
    Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N et al. 2018. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci. Transl. Med. 10:423eaai7795
    [Google Scholar]
  90. 90.
    Mencacci NE, Isaias IU, Reich MM, Ganos C, Plagnol V et al. 2014. Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. Brain 137:Part 92480–92
    [Google Scholar]
  91. 91.
    Ryan E, Seehra G, Sharma P, Sidransky E. 2019. GBA1-associated parkinsonism: new insights and therapeutic opportunities. Curr. Opin. Neurol. 32:4589–96
    [Google Scholar]
  92. 92.
    Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E. 2004. Parkinsonism among Gaucher disease carriers. J. Med. Genet. 41:12937–40
    [Google Scholar]
  93. 93.
    Blauwendraat C, Reed X, Krohn L, Heilbron K, Bandres-Ciga S et al. 2020. Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. Brain 143:1234–48
    [Google Scholar]
  94. 94.
    Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R et al. 2017. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain 140:123191–203
    [Google Scholar]
  95. 95.
    Straniero L, Rimoldi V, Monfrini E, Bonvegna S, Melistaccio G et al. 2022. Role of lysosomal gene variants in modulating GBA-associated Parkinson's disease risk. Mov. Disord. 37:61202–10
    [Google Scholar]
  96. 96.
    Alcalay RN, Mallett V, Vanderperre B, Tavassoly O, Dauvilliers Y et al. 2019. SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. Mov. Disord. 34:4526–35
    [Google Scholar]
  97. 97.
    Nalls MA, Blauwendraat C, Sargent L, Vitale D, Leonard H et al. 2021. Evidence for GRN connecting multiple neurodegenerative diseases. Brain Commun. 3:2fcab095
    [Google Scholar]
  98. 98.
    Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ et al. 2016. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov. Disord. 31:4436–57
    [Google Scholar]
  99. 99.
    Lubbe SJ, Escott-Price V, Gibbs JR, Nalls MA, Bras J et al. 2016. Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance. Hum. Mol. Genet. 25:245483–89
    [Google Scholar]
  100. 100.
    Bandres-Ciga S, Saez-Atienzar S, Kim JJ, Makarious MB, Faghri F et al. 2020. Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease. Acta Neuropathol. 140:3341–58
    [Google Scholar]
  101. 101.
    Iwaki H, Blauwendraat C, Makarious MB, Bandrés-Ciga S, Leonard HL et al. 2020. Penetrance of Parkinson's disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score. Mov. Disord. 35:5774–80
    [Google Scholar]
  102. 102.
    Simuni T, Uribe L, Cho HR, Caspell-Garcia C, Coffey CS et al. 2020. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 19:171–80
    [Google Scholar]
  103. 103.
    Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M et al. 2015. Differential effects of severe versus mild GBA mutations on Parkinson disease. Neurology 84:9880–87
    [Google Scholar]
  104. 104.
    Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S et al. 2016. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Ann. Neurol. 80:5674–85
    [Google Scholar]
  105. 105.
    Blauwendraat C, Heilbron K, Vallerga CL, Bandres-Ciga S, von Coelln R et al. 2019. Parkinson's disease age at onset genome-wide association study: defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34:6866–75
    [Google Scholar]
  106. 106.
    Pankratz N, Byder L, Halter C, Rudolph A, Shults CW et al. 2006. Presence of an APOE4 allele results in significantly earlier onset of Parkinson's disease and a higher risk with dementia. Mov. Disord. 21:145–49
    [Google Scholar]
  107. 107.
    Szwedo AA, Dalen I, Pedersen KF, Camacho M, Bäckström D et al. 2022. GBA and APOE impact cognitive decline in Parkinson's disease: a 10-year population-based study. Mov. Disord. 37:51016–27
    [Google Scholar]
  108. 108.
    Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM et al. 2020. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci. Transl. Med. 12:529eaay3069
    [Google Scholar]
  109. 109.
    Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B et al. 2020. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci. Transl. Med. 12:529eaay1809
    [Google Scholar]
  110. 110.
    Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH et al. 2021. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat. Genet. 53:3294–303
    [Google Scholar]
  111. 111.
    Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J et al. 2018. Analysis of shared heritability in common disorders of the brain. Science 360:6395eaap8757
    [Google Scholar]
  112. 112.
    Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC et al. 2016. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533:760195–99
    [Google Scholar]
  113. 113.
    Nguyen M, Wong YC, Ysselstein D, Severino A, Krainc D. 2019. Synaptic, mitochondrial, and lysosomal dysfunction in Parkinson's disease. Trends Neurosci. 42:2140–49
    [Google Scholar]
  114. 114.
    Panicker N, Ge P, Dawson VL, Dawson TM. 2021. The cell biology of Parkinson's disease. J. Cell Biol. 220:4e202012095
    [Google Scholar]
  115. 115.
    Runwal G, Edwards RH. 2021. The membrane interactions of synuclein: physiology and pathology. Annu. Rev. Pathol. Mech. Dis. 16:465–85
    [Google Scholar]
  116. 116.
    Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. 2010. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:59991663–67
    [Google Scholar]
  117. 117.
    Burré J, Sharma M, Südhof TC. 2012. Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities. J. Neurosci. 32:4315227–42
    [Google Scholar]
  118. 118.
    Doherty CPA, Ulamec SM, Maya-Martinez R, Good SC, Makepeace J et al. 2020. A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function. Nat. Struct. Mol. Biol. 27:3249–59
    [Google Scholar]
  119. 119.
    Piccoli G, Condliffe SB, Bauer M, Giesert F, Boldt K et al. 2011. LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J. Neurosci. 31:62225–37
    [Google Scholar]
  120. 120.
    Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W et al. 2012. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75:61008–21
    [Google Scholar]
  121. 121.
    Arranz AM, Delbroek L, van Kolen K, Guimarães MR, Mandemakers W et al. 2015. LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. J. Cell Sci. 128:3541–52
    [Google Scholar]
  122. 122.
    Beilina A, Rudenko IN, Kaganovich A, Civiero L, Chau H et al. 2014. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. PNAS 111:72626–31
    [Google Scholar]
  123. 123.
    Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V et al. 2013. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive parkinsonism with generalized seizures. Hum. Mutat. 34:91200–7
    [Google Scholar]
  124. 124.
    Edvardson S, Cinnamon Y, Ta-Shma A, Shaag A, Yim YI et al. 2012. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLOS ONE 7:5e36458
    [Google Scholar]
  125. 125.
    Islam MS, Nolte H, Jacob W, Ziegler AB, Pütz S et al. 2016. Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease. Hum. Mol. Genet. 25:245365–82
    [Google Scholar]
  126. 126.
    Verstreken P, Koh TW, Schulze KL, Zhai RG, Hiesinger PR et al. 2003. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 40:4733–48
    [Google Scholar]
  127. 127.
    Nguyen M, Krainc D. 2018. LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson's disease. PNAS 115:215576–81
    [Google Scholar]
  128. 128.
    MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G et al. 2013. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77:3425–39
    [Google Scholar]
  129. 129.
    Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM et al. 2011. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89:1162–67
    [Google Scholar]
  130. 130.
    Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH et al. 2011. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89:1168–75
    [Google Scholar]
  131. 131.
    Ye H, Ojelade SA, Li-Kroeger D, Zuo Z, Wang L et al. 2020. Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain. eLife 9:e51977
    [Google Scholar]
  132. 132.
    Munsie LN, Milnerwood AJ, Seibler P, Beccano-Kelly DA, Tatarnikov I et al. 2015. Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N. Hum. Mol. Genet. 24:61691–703
    [Google Scholar]
  133. 133.
    Di Maio R, Hoffman EK, Rocha EM, Keeney MT, Sanders LH et al. 2018. LRRK2 activation in idiopathic Parkinson's disease. Sci. Transl. Med. 10:451eaar5429
    [Google Scholar]
  134. 134.
    Khurana V, Peng J, Chung CY, Auluck PK, Fanning S et al. 2017. Genome-scale networks link neurodegenerative disease genes to α-synuclein through specific molecular pathways. Cell Syst. 4:2157–70.e14
    [Google Scholar]
  135. 135.
    Dhungel N, Eleuteri S, Li L-B, Kramer NJ, Chartron JW et al. 2015. Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein. Neuron 85:176–87
    [Google Scholar]
  136. 136.
    Pan PY, Sheehan P, Wang Q, Zhu X, Zhang Y et al. 2020. Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice. Hum. Mol. Genet. 29:142300–12
    [Google Scholar]
  137. 137.
    Song L, He Y, Ou J, Zhao Y, Li R et al. 2017. Auxilin underlies progressive locomotor deficits and dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Cell Rep. 18:51132–43
    [Google Scholar]
  138. 138.
    Chung CY, Khurana V, Yi S, Sahni N, Loh KH et al. 2017. In situ peroxidase labeling and mass-spectrometry connects alpha-synuclein directly to endocytic trafficking and mRNA metabolism in neurons. Cell Syst. 4:2242–50.e4
    [Google Scholar]
  139. 139.
    Ballabio A, Bonifacino JS. 2020. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21:2101–18
    [Google Scholar]
  140. 140.
    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. 2003. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278:2725009–13
    [Google Scholar]
  141. 141.
    Cuervo AM, Stafanis L, Fredenburg R, Lansbury PT, Sulzer D. 2004. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305:56881292–95
    [Google Scholar]
  142. 142.
    Wildburger NC, Hartke AS, Schidlitzki A, Richter F. 2020. Current evidence for a bidirectional loop between the lysosome and alpha-synuclein proteoforms. Front. Cell Dev. Biol. 8:598446
    [Google Scholar]
  143. 143.
    Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D. 2016. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. PNAS 113:71931–36
    [Google Scholar]
  144. 144.
    Senol AD, Samarani M, Syan S, Guardia CM, Nonaka T et al. 2021. α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. PLOS Biol 19:7e3001287
    [Google Scholar]
  145. 145.
    Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ et al. 2006. α-Synuclein blocks ER–Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313:5785324–28
    [Google Scholar]
  146. 146.
    Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS et al. 2014. Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson's disease. Brain 137:3834–48
    [Google Scholar]
  147. 147.
    Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B et al. 2015. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain 138:Part 92648–58
    [Google Scholar]
  148. 148.
    Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ et al. 2011. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:137–52
    [Google Scholar]
  149. 149.
    Henderson MX, Sedor S, McGeary I, Cornblath EJ, Peng C et al. 2020. Glucocerebrosidase activity modulates neuronal susceptibility to pathological α-synuclein insult. Neuron 105:5822–36.e7
    [Google Scholar]
  150. 150.
    Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I et al. 2018. Reversible conformational conversion of α-synuclein into toxic assemblies by glucosylceramide. Neuron 97:192–107.e10
    [Google Scholar]
  151. 151.
    Taguchi YV, Liu J, Ruan J, Pacheco J, Zhang X et al. 2017. Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinson's disease. J. Neurosci. 37:409617–31
    [Google Scholar]
  152. 152.
    Kuo SH, Tasset I, Cheng MM, Diaz A, Pan MK et al. 2022. Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy. Sci. Adv. 8:6eabm6393
    [Google Scholar]
  153. 153.
    Alcalay RN, Mallett V, Vanderperre B, Tavassoly O, Dauvilliers Y et al. 2019. SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. Mov. Disord. 34:4526–35
    [Google Scholar]
  154. 154.
    McGlinchey RP, Lee JC. 2015. Cysteine cathepsins are essential in lysosomal degradation of α-synuclein. PNAS 112:309322–27
    [Google Scholar]
  155. 155.
    Cang C, Aranda K, Seo YJ, Gasnier B, Ren D. 2015. TMEM175 is an organelle K+ channel regulating lysosomal function. Cell 162:51101–12
    [Google Scholar]
  156. 156.
    Zheng W, Shen C, Wang L, Rawson S, Xie WJ et al. 2022. pH regulates potassium conductance and drives a constitutive proton current in human TMEM175. Sci. Adv. 8:12eabm1568
    [Google Scholar]
  157. 157.
    Krohn L, Öztürk TN, Vanderperre B, Ouled Amar Bencheikh B, Ruskey JA et al. 2020. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies. Ann. Neurol. 87:1139–53
    [Google Scholar]
  158. 158.
    Jinn S, Blauwendraat C, Toolan D, Gretzula CA, Drolet RE et al. 2019. Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. Hum. Mol. Genet. 28:193244–54
    [Google Scholar]
  159. 159.
    Jinn S, Drolet RE, Cramer PE, Wong AHK, Toolan DM et al. 2017. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. PNAS 114:92389–94
    [Google Scholar]
  160. 160.
    Wie J, Liu Z, Song H, Tropea TF, Yang L et al. 2021. A growth-factor-activated lysosomal K+ channel regulates Parkinson's pathology. Nature 591:7850431–37
    [Google Scholar]
  161. 161.
    Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D et al. 2006. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38:101184–91
    [Google Scholar]
  162. 162.
    van Veen S, Martin S, Van den Haute C, Benoy V, Lyons J et al. 2020. ATP13A2 deficiency disrupts lysosomal polyamine export. Nature 578:7795419–24
    [Google Scholar]
  163. 163.
    Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S et al. 2009. α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet. 41:3308–15
    [Google Scholar]
  164. 164.
    Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG et al. 2019. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15:10565–81
    [Google Scholar]
  165. 165.
    Kim S, Wong YC, Gao F, Krainc D. 2021. Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson's disease. Nat. Commun. 12:11807
    [Google Scholar]
  166. 166.
    Lin G, Lee PT, Chen K, Mao D, Tan KL et al. 2018. Phospholipase PLA2G6, a parkinsonism-associated gene, affects Vps26 and Vps35, retromer function, and ceramide levels, similar to α-synuclein gain. Cell Metab. 28:4605–18.e6
    [Google Scholar]
  167. 167.
    Langston JW, Ballard P, Tetrud JW, Irwin I. 1983. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:4587979–80
    [Google Scholar]
  168. 168.
    Borsche M, Pereira SL, Klein C, Grünewald A. 2021. Mitochondria and Parkinson's disease: clinical, molecular, and translational aspects. J. Parkinsons Dis. 11:145–60
    [Google Scholar]
  169. 169.
    Park J, Lee SB, Lee S, Kim Y, Song S et al. 2006. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:70971157–61
    [Google Scholar]
  170. 170.
    Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR et al. 2006. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:70971162–66
    [Google Scholar]
  171. 171.
    Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA et al. 2010. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLOS Biol. 8:1e1000298
    [Google Scholar]
  172. 172.
    Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J et al. 2015. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 14:3274–82
    [Google Scholar]
  173. 173.
    Meng H, Yamashita C, Shiba-Fukushima K, Inoshita T, Funayama M et al. 2017. Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c. Nat. Commun. 8:15500
    [Google Scholar]
  174. 174.
    Baek M, Choe YJ, Bannwarth S, Kim J, Maitra S et al. 2021. TDP-43 and PINK1 mediate CHCHD10S59L mutation-induced defects in Drosophila and in vitro. Nat Commun. 12:11924
    [Google Scholar]
  175. 175.
    Billingsley KJ, Barbosa IA, Bandrés-Ciga S, Quinn JP, Bubb VJ et al. 2019. Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset. NPJ Parkinsons Dis 5:8
    [Google Scholar]
  176. 176.
    Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M et al. 2016. Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy. Am. J. Hum. Genet. 98:3500–13
    [Google Scholar]
  177. 177.
    Jansen IE, Ye H, Heetveld S, Lechler MC, Michels H et al. 2017. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biol 18:22
    [Google Scholar]
  178. 178.
    Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ. 2021. Mitochondrial dysfunction and mitophagy in Parkinson's disease: from mechanism to therapy. Trends Biochem. Sci. 46:4329–43
    [Google Scholar]
  179. 179.
    Chung E, Choi Y, Park J, Nah W, Park J et al. 2020. Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein. Sci. Adv. 6:18eaba1193
    [Google Scholar]
  180. 180.
    Devine MJ, Kittler JT. 2018. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19:263–80
    [Google Scholar]
  181. 181.
    Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC et al. 2017. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:63571255–61
    [Google Scholar]
  182. 182.
    Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E et al. 2017. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature 546:7660656–61
    [Google Scholar]
  183. 183.
    Lopes KdP, Snijders GJL, Humphrey J, Allan A, Sneeboer MAM et al. 2022. Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies. Nat. Genet. 54:14–17
    [Google Scholar]
  184. 184.
    Scheiblich H, Dansokho C, Mercan D, Schmidt SV, Bousset L et al. 2021. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell 184:205089–106.e21
    [Google Scholar]
  185. 185.
    Guo M, Wang J, Zhao Y, Feng Y, Han S et al. 2020. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain 143:51476–97
    [Google Scholar]
  186. 186.
    Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L et al. 2019. Intestinal infection triggers Parkinson's disease-like symptoms in Pink1−/− mice. Nature 571:7766565–69
    [Google Scholar]
  187. 187.
    Schneider SA, Hizli B, Alcalay RN. 2020. Emerging targeted therapeutics for genetic subtypes of parkinsonism. Neurotherapeutics 17:41378–92
    [Google Scholar]
  188. 188.
    Cook L, Schulze J, Kopil C, Hastings T, Naito A et al. 2021. Genetic testing for Parkinson disease: Are we ready?. Neurol. Clin. Pract. 11:169–77
    [Google Scholar]
  189. 189.
    Leveille E, Ross OA, Gan-Or Z. 2021. Tau and MAPT genetics in tauopathies and synucleinopathies. Parkinsonism Relat. Disord. 90:142–54
    [Google Scholar]
  190. 190.
    Trabzuni D, Wray S, Vandrovcova J, Ramasamy A, Walker R et al. 2012. MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum. Mol. Genet. 21:184094–103
    [Google Scholar]
  191. 191.
    Dong X, Liao Z, Gritsch D, Hadzhiev Y, Bai Y et al. 2018. Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease. Nat. Neurosci. 21:101482–92
    [Google Scholar]
  192. 192.
    Simone R, Javad F, Emmett W, Wilkins OG, Almeida FL et al. 2021. MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration. Nature 594:7861117–23
    [Google Scholar]
  193. 193.
    Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL et al. 2003. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:5619636–40
    [Google Scholar]
  194. 194.
    Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VMY. 2002. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34:4521–33
    [Google Scholar]
  195. 195.
    Lee MK, Stirling W, Xu Y, Xu E, Qui D et al. 2002. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. PNAS 99:138968–73
    [Google Scholar]
  196. 196.
    Feany MB, Bender WW. 2000. A Drosophila model of Parkinson's disease. Nature 404:6776394–98
    [Google Scholar]
  197. 197.
    Auluck PK, Chan HYE, Trojanowski JQ, Lee VMY, Bonini NM. 2002. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295:5556865–68
    [Google Scholar]
  198. 198.
    Hallacli E, Kayatekin C, Nazeen S, Wang XH, Sheinkopf Z et al. 2022. The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability. Cell 185:122035–56
    [Google Scholar]
  199. 199.
    Rousseaux MWC, Vázquez-Vélez GE, Al-Ramahi I, Jeong HH, Bajić A et al. 2018. A druggable genome screen identifies modifiers of α-synuclein levels via a tiered cross-species validation approach. J. Neurosci. 38:439286–301
    [Google Scholar]
/content/journals/10.1146/annurev-pathmechdis-031521-034145
Loading
/content/journals/10.1146/annurev-pathmechdis-031521-034145
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error