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Open Access 01-11-2019 | Pathology | Review

Selective vulnerability in α-synucleinopathies

Authors: Javier Alegre-Abarrategui, Katherine R. Brimblecombe, Rosalind F. Roberts, Elisavet Velentza-Almpani, Bension S. Tilley, Nora Bengoa-Vergniory, Christos Proukakis

Published in: Acta Neuropathologica | Issue 5/2019

Abstract

Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease. Different neuroanatomical regions and cellular populations manifest a differential vulnerability to the appearance of protein deposits, cell dysfunction, and cell death, leading to phenotypic diversity. The present review describes the multiple factors that contribute to the selective vulnerability in α-synucleinopathies. We explore the intrinsic cellular properties in the affected regions, including the physiological and pathophysiological roles of endogenous α-syn, the metabolic and genetic build-up of the cells and their connectivity. These factors converge with the variability of the α-syn conformational strains and their spreading capacity to dictate the phenotypic diversity and regional vulnerability of each disease. Finally, we describe the exogenous and environmental factors that potentially contribute by igniting and modulating the differential pathology in α-synucleinopathies. In conclusion, we think that it is the confluence of this disruption of the cellular metabolic state and α-syn structural equilibrium through the anatomical connectivity which appears to initiate cascades of pathological processes triggered by genetic, environmental, or stochastic events that result in the “death by a thousand cuts” profile of α-synucleinopathies.

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Aamodt AH, Stovner LJ, Thorstensen K, Lydersen S, White LR, Aasly JO (2007) Prevalence of haemochromatosis gene mutations in Parkinson’s disease. J Neurol Neurosurg Psychiatry 78:315–317. https://doi.org/10.1136/jnnp.2006.101352 CrossRefPubMed

Abeyawardhane DL, Fernandez RD, Murgas CJ, Heitger DR, Forney AK, Crozier MK et al (2018) Iron redox chemistry promotes antiparallel oligomerization of alpha-synuclein. J Am Chem Soc 140:5028–5032. https://doi.org/10.1021/jacs.8b02013 CrossRefPubMed

Acosta SA, Tajiri N, de la Pena I, Bastawrous M, Sanberg PR, Kaneko Y et al (2015) Alpha-synuclein as a pathological link between chronic traumatic brain injury and Parkinson’s disease. J Cell Physiol 230:1024–1032. https://doi.org/10.1002/jcp.24830 CrossRefPubMedPubMedCentral

Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Grimmig B, Diamond DM et al (2013) Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One 8:e53376. https://doi.org/10.1371/journal.pone.0053376 CrossRefPubMedPubMedCentral

Alegre-Abarrategui J, Ansorge O, Esiri M, Wade-Martins R (2008) LRRK2 is a component of granular alpha-synuclein pathology in the brainstem of Parkinson’s disease. Neuropathol Appl Neurobiol 34:272–283. https://doi.org/10.1111/j.1365-2990.2007.00888.x CrossRefPubMed

Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O et al (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18:4022–4034. https://doi.org/10.1093/hmg/ddp346 CrossRefPubMedPubMedCentral

Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA et al (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67:1464–1472. https://doi.org/10.1001/archneurol.2010.198 CrossRefPubMed

Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T et al (2014) Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62:964–970. https://doi.org/10.1002/glia.22653 CrossRefPubMedPubMedCentral

Bahar E, Lee GH, Bhattarai KR, Lee HY, Choi MK, Rashid HO et al (2017) Polyphenolic extract of Euphorbia supina attenuates manganese-induced neurotoxicity by enhancing antioxidant activity through regulation of ER stress and ER stress-mediated apoptosis. Int J Mol Sci 18:300. https://doi.org/10.3390/ijms18020300 CrossRefPubMedCentral

10.

Ballard PA, Tetrud JW, Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 35:949–956CrossRefPubMed

11.

Bartels T, Ahlstrom LS, Leftin A, Kamp F, Haass C, Brown MF et al (2010) The N-terminus of the intrinsically disordered protein alpha-synuclein triggers membrane binding and helix folding. Biophys J 99:2116–2124. https://doi.org/10.1016/j.bpj.2010.06.035 CrossRefPubMedPubMedCentral

12.

Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634. https://doi.org/10.1007/s00401-009-0538-8 CrossRefPubMedPubMedCentral

13.

Bencsik A, Muselli L, Leboidre M, Lakhdar L, Baron T (2014) Early and persistent expression of phosphorylated alpha-synuclein in the enteric nervous system of A53T mutant human alpha-synuclein transgenic mice. J Neuropathol Exp Neurol 73:1144–1151. https://doi.org/10.1097/NEN.0000000000000137 CrossRefPubMed

14.

Benskey MJ, Perez RG, Manfredsson FP (2016) The contribution of alpha synuclein to neuronal survival and function—implications for Parkinson’s disease. J Neurochem 137:331–359. https://doi.org/10.1111/jnc.13570 CrossRefPubMedPubMedCentral

15.

Berchowitz Luke E, Kabachinski G, Walker Margaret R, Carlile Thomas M, Gilbert Wendy V, Schwartz Thomas U et al (2015) Regulated formation of an amyloid-like translational repressor governs gametogenesis. Cell 163:406–418. https://doi.org/10.1016/j.cell.2015.08.060 CrossRefPubMedPubMedCentral

16.

Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306. https://doi.org/10.1038/81834 CrossRefPubMed

17.

Bisaglia M, Tosatto L, Munari F, Tessari I, de Laureto PP, Mammi S et al (2010) Dopamine quinones interact with alpha-synuclein to form unstructured adducts. Biochem Biophys Res Commun 394:424–428. https://doi.org/10.1016/j.bbrc.2010.03.044 CrossRefPubMed

18.

Blauwendraat C, Kia DA, Pihlstrøm L, Gan-Or Z, Lesage S, Gibbs JR et al (2018) Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson’s disease. Neurobiol Aging 64:159.e155–159.e158. https://doi.org/10.1016/j.neurobiolaging.2017.12.012 CrossRef

19.

Boeve BF, Dickson DW, Olson EJ, Shepard JW, Silber MH, Ferman TJ et al (2007) Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 8:60–64. https://doi.org/10.1016/j.sleep.2006.08.017 CrossRefPubMed

20.

Boissard R, Fort P, Gervasoni D, Barbagli B, Luppi PH (2003) Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur J Neurosci 18:1627–1639CrossRefPubMed

21.

Bolam JP, Pissadaki EK (2012) Living on the edge with too many mouths to feed: why dopamine neurons die. Mov Disord 27:1478–1483. https://doi.org/10.1002/mds.25135 CrossRefPubMedPubMedCentral

22.

Book A, Guella I, Candido T, Brice A, Hattori N, Jeon B et al (2018) A meta-analysis of alpha-synuclein multiplication in familial parkinsonism. Front Neurol 9:1021. https://doi.org/10.3389/fneur.2018.01021 CrossRefPubMedPubMedCentral

23.

Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, Habenstein B et al (2013) Structural and functional characterization of two alpha-synuclein strains. Nat Commun 4:2575. https://doi.org/10.1038/ncomms3575 CrossRefPubMed

24.

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMed

25.

Braak H, Sastre M, Del Tredici K (2007) Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 114:231–241. https://doi.org/10.1007/s00401-007-0244-3 CrossRefPubMed

26.

Bradl M, Lassmann H (2010) Oligodendrocytes: biology and pathology. Acta Neuropathol 119:37–53. https://doi.org/10.1007/s00401-009-0601-5 CrossRefPubMed

27.

Bridi JC, Hirth F (2018) Mechanisms of alpha-synuclein induced synaptopathy in Parkinson’s disease. Front Neurosci 12:80. https://doi.org/10.3389/fnins.2018.00080 CrossRefPubMedPubMedCentral

28.

Brimblecombe KR, Cragg SJ (2017) The striosome and matrix compartments of the striatum: a path through the labyrinth from neurochemistry toward function. ACS Chem Neurosci 8:235–242. https://doi.org/10.1021/acschemneuro.6b00333 CrossRefPubMed

29.

Brimblecombe KR, Gracie CJ, Platt NJ, Cragg SJ (2015) Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. J Physiol 593:929–946. https://doi.org/10.1113/jphysiol.2014.285890 CrossRefPubMedPubMedCentral

30.

Bruinsma IB, Bruggink KA, Kinast K, Versleijen AA, Segers-Nolten IM, Subramaniam V et al (2011) Inhibition of alpha-synuclein aggregation by small heat shock proteins. Proteins 79:2956–2967. https://doi.org/10.1002/prot.23152 CrossRefPubMed

31.

Bu B, Tong X, Li D, Hu Y, He W, Zhao C et al (2017) N-terminal acetylation preserves alpha-synuclein from oligomerization by blocking intermolecular hydrogen bonds. ACS Chem Neurosci 8:2145–2151. https://doi.org/10.1021/acschemneuro.7b00250 CrossRefPubMed

32.

Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S et al (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357:1255–1261. https://doi.org/10.1126/science.aam9080 CrossRefPubMedPubMedCentral

33.

Burre J, Sharma M, Sudhof TC (2014) alpha-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci USA 111:E4274–4283. https://doi.org/10.1073/pnas.1416598111 CrossRefPubMedPubMedCentral

34.

Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC (2013) Properties of native brain α-synuclein. Nature 498:E4–E7. https://doi.org/10.1038/nature12125 CrossRefPubMedPubMedCentral

35.

Carriere CH, Kang NH, Niles LP (2017) Bilateral upregulation of alpha-synuclein expression in the mouse substantia nigra by intracranial rotenone treatment. Exp Toxicol Pathol 69:109–114. https://doi.org/10.1016/j.etp.2016.12.007 CrossRefPubMed

36.

Castillo-Gonzalez JA, Loera-Arias MJ, Saucedo-Cardenas O, Montes-de-Oca-Luna R, Garcia-Garcia A, Rodriguez-Rocha H (2017) Phosphorylated alpha-synuclein–copper complex formation in the pathogenesis of Parkinson’s disease. Parkinsons Dis 2017:9164754. https://doi.org/10.1155/2017/9164754 CrossRefPubMedPubMedCentral

37.

Cavaliere F, Cerf L, Dehay B, Ramos-Gonzalez P, De Giorgi F, Bourdenx M et al (2017) In vitro alpha-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol Dis 103:101–112. https://doi.org/10.1016/j.nbd.2017.04.011 CrossRefPubMed

38.

Chadchankar H, Ihalainen J, Tanila H, Yavich L (2011) Decreased reuptake of dopamine in the dorsal striatum in the absence of alpha-synuclein. Brain Res 1382:37–44. https://doi.org/10.1016/j.brainres.2011.01.064 CrossRefPubMed

39.

Chang D, Nalls MA, Hallgrimsdottir IB, Hunkapiller J, van der Brug M, Cai F et al (2017) A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 49:1511–1516. https://doi.org/10.1038/ng.3955 CrossRefPubMedPubMedCentral

40.

Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello MM, Bowman AB et al (2015) Manganese homeostasis in the nervous system. J Neurochem 134:601–610. https://doi.org/10.1111/jnc.13170 CrossRefPubMedPubMedCentral

41.

Chen P, Miah, Aschner M (2016) Metals and neurodegeneration. F1000Res 5:1000. https://doi.org/10.12688/f1000research.7431.1 CrossRef

42.

Chronister WD, Burbulis IE, Wierman MB, Wolpert MJ, Haakenson MF, Smith ACB et al (2019) Neurons with complex karyotypes are rare in aged human neocortex. Cell Rep 26:825–835 e827. https://doi.org/10.1016/j.celrep.2018.12.107 CrossRefPubMedPubMedCentral

43.

GTEx Consortium, Laboratory Data Analysis and Coordinating Center-Analysis Working Group, Statistical Methods Groups-Analysis Working Group, Enhancing GTEx Group, NIH Common Fund, NIH/NCI et al (2017) Genetic effects on gene expression across human tissues. Nature 550:204–213. https://doi.org/10.1038/nature24277 CrossRef

44.

Cremades N, Cohen SI, Deas E, Abramov AY, Chen AY, Orte A et al (2012) Direct observation of the interconversion of normal and toxic forms of alpha-synuclein. Cell 149:1048–1059. https://doi.org/10.1016/j.cell.2012.03.037 CrossRefPubMedPubMedCentral

45.

Crow ET, Li L (2011) Newly identified prions in budding yeast, and their possible functions. Semin Cell Dev Biol 22:452–459. https://doi.org/10.1016/j.semcdb.2011.03.003 CrossRefPubMedPubMedCentral

46.

Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295. https://doi.org/10.1126/science.1101738 CrossRefPubMed

47.

Cusanovich DA, Hill AJ, Aghamirzaie D, Daza RM, Pliner HA, Berletch JB et al (2018) A single-cell atlas of in vivo mammalian chromatin accessibility. Cell 174(1309–1324):e1318. https://doi.org/10.1016/j.cell.2018.06.052 CrossRef

48.

Cykowski MD, Coon EA, Powell SZ, Jenkins SM, Benarroch EE, Low PA et al (2015) Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain 138:2293–2309. https://doi.org/10.1093/brain/awv114 CrossRefPubMedPubMedCentral

49.

Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A et al (2007) Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 27:9220–9232. https://doi.org/10.1523/JNEUROSCI.2617-07.2007 CrossRefPubMedPubMedCentral

50.

Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE et al (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 99:14524–14529. https://doi.org/10.1073/pnas.172514599 CrossRefPubMedPubMedCentral

51.

Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L et al (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106:13010–13015. https://doi.org/10.1073/pnas.0903691106 CrossRefPubMedPubMedCentral

52.

Dettmer U, Newman AJ, Soldner F, Luth ES, Kim NC, von Saucken VE et al (2015) Parkinson-causing alpha-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun 6:7314. https://doi.org/10.1038/ncomms8314 CrossRefPubMed

53.

Djelloul M, Holmqvist S, Boza-Serrano A, Azevedo C, Yeung MS, Goldwurm S et al (2015) Alpha-synuclein expression in the oligodendrocyte lineage: an in vitro and in vivo study using rodent and human models. Stem Cell Rep 5:174–184. https://doi.org/10.1016/j.stemcr.2015.07.002 CrossRef

54.

Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE et al (2013) Parkin disease: a clinicopathologic entity? JAMA Neurol 70:571–579. https://doi.org/10.1001/jamaneurol.2013.172 CrossRefPubMedPubMedCentral

55.

Dolle C, Flones I, Nido GS, Miletic H, Osuagwu N, Kristoffersen S et al (2016) Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease. Nat Commun 7:13548. https://doi.org/10.1038/ncomms13548 CrossRefPubMedPubMedCentral

56.

Dong X, Liao Z, Gritsch D, Hadzhiev Y, Bai Y, Locascio JJ et al (2018) Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease. Nat Neurosci 21:1482–1492. https://doi.org/10.1038/s41593-018-0223-0 CrossRefPubMedPubMedCentral

57.

Du Z, Park KW, Yu H, Fan Q, Li L (2008) Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae. Nat Genet 40:460–465. https://doi.org/10.1038/ng.112 CrossRefPubMedPubMedCentral

58.

Duffy MF, Collier TJ, Patterson JR, Kemp CJ, Luk KC, Tansey MG et al (2018) Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J Neuroinflammation 15:129. https://doi.org/10.1186/s12974-018-1171-z CrossRefPubMedPubMedCentral

59.

Emamzadeh FN (2016) Alpha-synuclein structure, functions, and interactions. J Res Med Sci 21:29. https://doi.org/10.4103/1735-1995.181989 CrossRefPubMedPubMedCentral

60.

Engelender S, Isacson O (2017) The threshold theory for Parkinson’s disease. Trends Neurosci 40:4–14. https://doi.org/10.1016/j.tins.2016.10.008 CrossRefPubMed

61.

Ferreira SA, Romero-Ramos M (2018) Microglia response during Parkinson’s disease: alpha-synuclein intervention. Front Cell Neurosci 12:247. https://doi.org/10.3389/fncel.2018.00247 CrossRefPubMedPubMedCentral

62.

Finucane HK, Reshef YA, Anttila V, Slowikowski K, Gusev A, Byrnes A et al (2018) Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet 50:621–629. https://doi.org/10.1038/s41588-018-0081-4 CrossRefPubMedPubMedCentral

63.

Flagmeier P, Meisl G, Vendruscolo M, Knowles TP, Dobson CM, Buell AK et al (2016) Mutations associated with familial Parkinson’s disease alter the initiation and amplification steps of alpha-synuclein aggregation. Proc Natl Acad Sci USA 113:10328–10333. https://doi.org/10.1073/pnas.1604645113 CrossRefPubMedPubMedCentral

64.

Flones IH, Fernandez-Vizarra E, Lykouri M, Brakedal B, Skeie GO, Miletic H et al (2018) Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. Acta Neuropathol 135:409–425. https://doi.org/10.1007/s00401-017-1794-7 CrossRefPubMed

65.

Fountaine TM, Wade-Martins R (2007) RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. J Neurosci Res 85:351–363. https://doi.org/10.1002/jnr.21125 CrossRefPubMed

66.

Fukushima T, Tan X, Luo Y, Kanda H (2011) Serum vitamins and heavy metals in blood and urine, and the correlations among them in Parkinson’s disease patients in China. Neuroepidemiology 36:240–244. https://doi.org/10.1159/000328253 CrossRefPubMed

67.

Gaare JJ, Nido GS, Sztromwasser P, Knappskog PM, Dahl O, Lund-Johansen M et al (2018) Rare genetic variation in mitochondrial pathways influences the risk for Parkinson’s disease. Mov Disord 33:1591–1600. https://doi.org/10.1002/mds.64 CrossRefPubMedPubMedCentral

68.

Gerfen CR, Baimbridge KG, Miller JJ (1985) The neostriatal mosaic: compartmental distribution of calcium-binding protein and parvalbumin in the basal ganglia of the rat and monkey. Proc Natl Acad Sci USA 82:8780–8784CrossRefPubMedPubMedCentral

69.

Geula C, Bu J, Nagykery N, Scinto LFM, Chan J, Joseph J et al (2003) Loss of calbindin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss. F1000Res 455:249–259. https://doi.org/10.1002/cne.10475 CrossRef

70.

Goedert M, Jakes R, Spillantini MG (2017) The synucleinopathies: twenty years on. J Parkinsons Dis 7:S51–S69. https://doi.org/10.3233/JPD-179005 CrossRefPubMedPubMedCentral

71.

Greenamyre JT, Betarbet R, Sherer TB (2003) The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat Disord 9(Suppl 2):S59–64CrossRefPubMed

72.

Greten-Harrison B, Polydoro M, Morimoto-Tomita M, Diao L, Williams AM, Nie EH et al (2010) alphabetagamma-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc Natl Acad Sci USA 107:19573–19578. https://doi.org/10.1073/pnas.1005005107 CrossRefPubMedPubMedCentral

73.

Grunewald A, Rygiel KA, Hepplewhite PD, Morris CM, Picard M, Turnbull DM (2016) Mitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons. Ann Neurol 79:366–378. https://doi.org/10.1002/ana.24571 CrossRefPubMedPubMedCentral

74.

Gu M, Owen AD, Toffa SE, Cooper JM, Dexter DT, Jenner P et al (1998) Mitochondrial function, GSH and iron in neurodegeneration and Lewy body diseases. J Neurol Sci 158:24–29CrossRefPubMed

75.

Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B et al (2013) Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154:103–117. https://doi.org/10.1016/j.cell.2013.05.057 CrossRefPubMed

76.

Gureviciene I, Gurevicius K, Tanila H (2007) Role of alpha-synuclein in synaptic glutamate release. Neurobiol Dis 28:83–89. https://doi.org/10.1016/j.nbd.2007.06.016 CrossRefPubMed

77.

Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ (2009) Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci 29:11011–11019. https://doi.org/10.1523/JNEUROSCI.2519-09.2009 CrossRefPubMedPubMedCentral

78.

Halliday G, Herrero MT, Murphy K, McCann H, Ros-Bernal F, Barcia C et al (2009) No Lewy pathology in monkeys with over 10 years of severe MPTP Parkinsonism. Mov Disord 24:1519–1523. https://doi.org/10.1002/mds.22481 CrossRefPubMed

79.

Harischandra DS, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2015) alpha-Synuclein protects against manganese neurotoxic insult during the early stages of exposure in a dopaminergic cell model of Parkinson’s disease. Toxicol Sci 143:454–468. https://doi.org/10.1093/toxsci/kfu247 CrossRefPubMed

80.

Hastings MH, Goedert M (2013) Circadian clocks and neurodegenerative diseases: time to aggregate? Curr Opin Neurobiol 23:880–887. https://doi.org/10.1016/j.conb.2013.05.004 CrossRefPubMedPubMedCentral

81.

Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614. https://doi.org/10.1111/j.1365-2990.2007.00874.x CrossRefPubMedPubMedCentral

82.

Herrera A, Munoz P, Steinbusch HWM, Segura-Aguilar J (2017) Are dopamine oxidation metabolites involved in the loss of dopaminergic neurons in the nigrostriatal system in Parkinson’s disease? ACS Chem Neurosci 8:702–711. https://doi.org/10.1021/acschemneuro.7b00034 CrossRefPubMed

83.

Hoglinger GU, Breunig JJ, Depboylu C, Rouaux C, Michel PP, Alvarez-Fischer D et al (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson’s disease. Proc Natl Acad Sci USA 104:3585–3590. https://doi.org/10.1073/pnas.0611671104 CrossRefPubMedPubMedCentral

84.

Hook PW, McClymont SA, Cannon GH, Law WD, Morton AJ, Goff LA et al (2018) Single-cell RNA-seq of mouse dopaminergic neurons informs candidate gene selection for sporadic Parkinson disease. Am J Hum Genet 102:427–446. https://doi.org/10.1016/j.ajhg.2018.02.001 CrossRefPubMedPubMedCentral

85.

Impellizzeri D, Campolo M, Bruschetta G, Crupi R, Cordaro M, Paterniti I et al (2016) Traumatic brain injury leads to development of Parkinson’s disease related pathology in mice. Front Neurosci 10:458. https://doi.org/10.3389/fnins.2016.00458 CrossRefPubMedPubMedCentral

86.

Iranzo A, Santamaria J, Rye DB, Valldeoriola F, Marti MJ, Munoz E et al (2005) Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology 65:247–252. https://doi.org/10.1212/01.wnl.0000168864.97813.e0 CrossRefPubMed

87.

Janezic S, Threlfell S, Dodson PD, Dowie MJ, Taylor TN, Potgieter D et al (2013) Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci USA 110:E4016–4025. https://doi.org/10.1073/pnas.1309143110 CrossRefPubMedPubMedCentral

88.

Kaindlstorfer C, Jellinger KA, Eschlbock S, Stefanova N, Weiss G, Wenning GK (2018) The relevance of iron in the pathogenesis of multiple system atrophy: a viewpoint. J Alzheimer’s Dis 61:1253–1273. https://doi.org/10.3233/JAD-170601 CrossRef

89.

Kaji S, Maki T, Kinoshita H, Uemura N, Ayaki T, Kawamoto Y et al (2018) Pathological endogenous alpha-synuclein accumulation in oligodendrocyte precursor cells potentially induces inclusions in multiple system atrophy. Stem Cell Rep 10:356–365. https://doi.org/10.1016/j.stemcr.2017.12.001 CrossRef

90.

Katsuse O, Iseki E, Marui W, Kosaka K (2003) Developmental stages of cortical Lewy bodies and their relation to axonal transport blockage in brains of patients with dementia with Lewy bodies. J Neurol Sci 211:29–35CrossRefPubMed

91.

Kiely AP, Ling H, Asi YT, Kara E, Proukakis C, Schapira AH et al (2015) Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Mol Neurodegener 10:41. https://doi.org/10.1186/s13024-015-0038-3 CrossRefPubMedPubMedCentral

92.

Killinger BA, Labrie V (2017) Vertebrate food products as a potential source of prion-like α-synuclein. NPJ Parkinson’s Dis 3:33. https://doi.org/10.1038/s41531-017-0035-z CrossRef

93.

Konno T, Ross OA, Puschmann A, Dickson DW, Wszolek ZK (2016) Autosomal dominant Parkinson’s disease caused by SNCA duplications. Parkinsonism Relat Disord 22:S1–S6. https://doi.org/10.1016/j.parkreldis.2015.09.007 CrossRefPubMed

94.

Koros C, Stamelou M, Simitsi A, Beratis I, Papadimitriou D, Papagiannakis N et al (2018) Selective cognitive impairment and hyposmia in p. A53T SNCA PD vs typical PD. Neurology 90:e864–e869. https://doi.org/10.1212/wnl.0000000000005063 CrossRefPubMed

95.

Kosaka K (1978) Lewy bodies in cerebral cortex, report of three cases. Acta Neuropathol 42:127–134CrossRefPubMed

96.

Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M (2015) Manganese-induced parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health 12:7519–7540. https://doi.org/10.3390/ijerph120707519 CrossRefPubMedPubMedCentral

97.

Lake BB, Chen S, Sos BC, Fan J, Kaeser GE, Yung YC et al (2018) Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat Biotechnol 36:70–80. https://doi.org/10.1038/nbt.4038 CrossRefPubMed

98.

Lam HA, Wu N, Cely I, Kelly RL, Hean S, Richter F et al (2011) Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human alpha-synuclein. J Neurosci Res 89:1091–1102. https://doi.org/10.1002/jnr.22611 CrossRefPubMedPubMedCentral

99.

Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S et al (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272. https://doi.org/10.1074/jbc.M109.081125 CrossRefPubMedPubMedCentral

100.

Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ et al (2018) Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563:639–645. https://doi.org/10.1038/s41586-018-0718-6 CrossRefPubMedPubMedCentral

101.

Lee SK, Sillitoe RV, Silva C, Martina M, Sekerkova G (2015) alpha-Synuclein expression in the mouse cerebellum is restricted to VGluT1 excitatory terminals and is enriched in unipolar brush cells. Cerebellum 14:516–527. https://doi.org/10.1007/s12311-015-0673-9 CrossRefPubMedPubMedCentral

102.

Levy Nogueira M, Hamraz M, Abolhassani M, Bigan E, Lafitte O, Steyaert JM et al (2018) Mechanical stress increases brain amyloid beta, tau, and alpha-synuclein concentrations in wild-type mice. Alzheimer’s Dementia 14:444–453. https://doi.org/10.1016/j.jalz.2017.11.003 CrossRefPubMed

103.

Li L, McGinnis JP, Si K (2018) Translational control by prion-like proteins. Trends Cell Biol 28:494–505CrossRefPubMedPubMedCentral

104.

Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA et al (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278:8516–8525. https://doi.org/10.1074/jbc.M210432200 CrossRefPubMed

105.

Lionnet A, Leclair-Visonneau L, Neunlist M, Murayama S, Takao M, Adler CH et al (2018) Does Parkinson’s disease start in the gut? Acta Neuropathol 135:1–12. https://doi.org/10.1007/s00401-017-1777-8 CrossRefPubMed

106.

Liu C, Kershberg L, Wang J, Schneeberger S, Kaeser PS (2018) Dopamine secretion is mediated by sparse active zone-like release sites. Cell 172(706–718):e715. https://doi.org/10.1016/j.cell.2018.01.008 CrossRef

107.

Ludtmann MHR, Angelova PR, Horrocks MH, Choi ML, Rodrigues M, Baev AY et al (2018) Alpha-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nat Commun 9:2293. https://doi.org/10.1038/s41467-018-04422-2 CrossRefPubMedPubMedCentral

108.

Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ et al (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953. https://doi.org/10.1126/science.1227157 CrossRefPubMedPubMedCentral

109.

Luk KC, Song C, O’Brien P, Stieber A, Branch JR, Brunden KR et al (2009) Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci USA 106:20051–20056. https://doi.org/10.1073/pnas.0908005106 CrossRefPubMedPubMedCentral

110.

March ZM, King OD, Shorter J (2016) Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease. Brain Res 1647:9–18. https://doi.org/10.1016/j.brainres.2016.02.037 CrossRefPubMedPubMedCentral

111.

Masliah E, Dumaop W, Galasko D, Desplats P (2013) Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 8:1030–1038. https://doi.org/10.4161/epi.25865 CrossRefPubMedPubMedCentral

112.

Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H et al (2013) Prion-like spreading of pathological alpha-synuclein in brain. Brain 136:1128–1138. https://doi.org/10.1093/brain/awt037 CrossRefPubMedPubMedCentral

113.

Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S et al (2010) CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS One 5:e15522. https://doi.org/10.1371/journal.pone.0015522 CrossRefPubMedPubMedCentral

114.

McConnell MJ, Moran JV, Abyzov A, Akbarian S, Bae T, Cortes-Ciriano I et al (2017) Intersection of diverse neuronal genomes and neuropsychiatric disease: the Brain Somatic Mosaicism Network. Science. https://doi.org/10.1126/science.aal1641 CrossRefPubMedPubMedCentral

115.

McCormack AL, Mak SK, Shenasa M, Langston WJ, Forno LS, Di Monte DA (2008) Pathologic modifications of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. J Neuropathol Exp Neurol 67:793–802. https://doi.org/10.1097/NEN.0b013e318180f0bd CrossRefPubMed

116.

McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA et al (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127CrossRefPubMed

117.

McCowan PK (1932) Encephalitis lethargica: its sequelæ and treatment. By Constantine von Economo. Translated and adapted by K. O. Newman. Oxford University Press (Humphrey Milford), 1931. Pp. 216. With 21 illustrations. Price 18s. net. J Ment Sci 78:395–396. https://doi.org/10.1192/bjp.78.321.395 CrossRef

118.

Mendez I, Viñuela A, Astradsson A, Mukhida K, Hallett P, Robertson H et al (2008) Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med 14:507. https://doi.org/10.1038/nm1752 CrossRefPubMedPubMedCentral

119.

Milanese C, Cerri S, Ulusoy A, Gornati SV, Plat A, Gabriels S et al (2018) Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease. Cell Death Dis 9:818. https://doi.org/10.1038/s41419-018-0848-7 CrossRefPubMedPubMedCentral

120.

Mokretar K, Pease D, Taanman JW, Soenmez A, Ejaz A, Lashley T et al (2018) Somatic copy number gains of alpha-synuclein (SNCA) in Parkinson’s disease and multiple system atrophy brains. Brain. https://doi.org/10.1093/brain/awy157 CrossRefPubMed

121.

More SV, Kumar H, Kim IS, Song SY, Choi DK (2013) Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson’s disease. Mediat Inflamm 2013:952375. https://doi.org/10.1155/2013/952375 CrossRef

122.

Nasstrom T, Fagerqvist T, Barbu M, Karlsson M, Nikolajeff F, Kasrayan A et al (2011) The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of alpha-synuclein oligomers with distinct biochemical, morphological, and functional properties. Free Radic Biol Med 50:428–437. https://doi.org/10.1016/j.freeradbiomed.2010.11.027 CrossRefPubMed

123.

Naudet N, Antier E, Gaillard D, Morignat E, Lakhdar L, Baron T et al (2017) Oral exposure to paraquat triggers earlier expression of phosphorylated alpha-synuclein in the enteric nervous system of A53T mutant human alpha-synuclein transgenic mice. J Neuropathol Exp Neurol 76:1046–1057. https://doi.org/10.1093/jnen/nlx092 CrossRefPubMedPubMedCentral

124.

Nielsen JE, Jensen LN, Krabbe K (1995) Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome. J Neurol Neurosurg Psychiatry 59:318–321CrossRefPubMedPubMedCentral

125.

Norris EH, Uryu K, Leight S, Giasson BI, Trojanowski JQ, Lee VM (2007) Pesticide exposure exacerbates alpha-synucleinopathy in an A53T transgenic mouse model. Am J Pathol 170:658–666. https://doi.org/10.2353/ajpath.2007.060359 CrossRefPubMedPubMedCentral

126.

Nussbaum RL (2017) The identification of alpha-synuclein as the first Parkinson disease gene. J Parkinsons Dis 7:S43–S49. https://doi.org/10.3233/JPD-179003 CrossRefPubMedPubMedCentral

127.

Okuzumi A, Kurosawa M, Hatano T, Takanashi M, Nojiri S, Fukuhara T et al (2018) Rapid dissemination of alpha-synuclein seeds through neural circuits in an in vivo prion-like seeding experiment. Acta Neuropathol Commun 6:96. https://doi.org/10.1186/s40478-018-0587-0 CrossRefPubMedPubMedCentral

128.

Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K et al (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131:642–650. https://doi.org/10.1093/brain/awm302 CrossRefPubMed

129.

Paisán-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, Kidd D et al (2012) Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 33:814–823. https://doi.org/10.1016/j.neurobiolaging.2010.05.009 CrossRefPubMedPubMedCentral

130.

Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O’Sullivan GA, Pal A et al (2012) Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2:898. https://doi.org/10.1038/srep00898 CrossRefPubMedPubMedCentral

131.

Parkkinen L, O’Sullivan SS, Collins C, Petrie A, Holton JL, Revesz T et al (2011) Disentangling the relationship between Lewy bodies and nigral neuronal loss in Parkinson’s disease. J Parkinsons Dis 1:277–286. https://doi.org/10.3233/JPD-2011-11046 CrossRefPubMedPubMedCentral

132.

Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J et al (2014) A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol Aging 35:2180.e2181–2180.e2185. https://doi.org/10.1016/j.neurobiolaging.2014.03.024 CrossRef

133.

Pavlou MAS, Pinho R, Paiva I, Outeiro TF (2017) The yin and yang of alpha-synuclein-associated epigenetics in Parkinson’s disease. Brain 140:878–886. https://doi.org/10.1093/brain/aww227 CrossRefPubMed

134.

Peelaerts W, Bousset L, Baekelandt V, Melki R (2018) α-Synuclein strains and seeding in Parkinson’s disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences. Cell Tissue Res 373:195–212. https://doi.org/10.1007/s00441-018-2839-5 CrossRefPubMed

135.

Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M et al (2015) Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344. https://doi.org/10.1038/nature14547 CrossRefPubMed

136.

Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL et al (2018) Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies. Nature 557:558–563. https://doi.org/10.1038/s41586-018-0104-4 CrossRefPubMedPubMedCentral

137.

Pihlstrom L, Blauwendraat C, Cappelletti C, Berge-Seidl V, Langmyhr M, Henriksen SP et al (2018) A comprehensive analysis of SNCA-related genetic risk in sporadic Parkinson disease. Ann Neurol 84:117–129. https://doi.org/10.1002/ana.25274 CrossRefPubMedPubMedCentral

138.

Post MR, Lieberman OJ, Mosharov EV (2018) Can interactions between alpha-synuclein, dopamine and calcium explain selective neurodegeneration in Parkinson’s disease? Front Neurosci 12:161. https://doi.org/10.3389/fnins.2018.00161 CrossRefPubMedPubMedCentral

139.

Poulopoulos M, Levy OA, Alcalay RN (2012) The neuropathology of genetic Parkinson’s disease. Mov Disord 27:831–842. https://doi.org/10.1002/mds.24962 CrossRefPubMedPubMedCentral

140.

Pountney DL, Lowe R, Quilty M, Vickers JC, Voelcker NH, Gai WP (2004) Annular alpha-synuclein species from purified multiple system atrophy inclusions. J Neurochem 90:502–512. https://doi.org/10.1111/j.1471-4159.2004.02533.x CrossRefPubMed

141.

Power JH, Barnes OL, Chegini F (2017) Lewy bodies and the mechanisms of neuronal cell death in Parkinson’s disease and dementia with Lewy bodies. Brain Pathol 27:3–12. https://doi.org/10.1111/bpa.12344 CrossRefPubMed

142.

Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL et al (2013) A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80:1062–1064. https://doi.org/10.1212/WNL.0b013e31828727ba CrossRefPubMedPubMedCentral

143.

Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB et al (2015) Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308–5317. https://doi.org/10.1073/pnas.1514475112 CrossRefPubMedPubMedCentral

144.

Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA (2005) Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis 20:898–906. https://doi.org/10.1016/j.nbd.2005.05.028 CrossRefPubMed

145.

Ramachandiran S, Hansen JM, Jones DP, Richardson JR, Miller GW (2007) Divergent mechanisms of paraquat, MPP⁺, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation. Toxicol Sci 95:163–171. https://doi.org/10.1093/toxsci/kfl125 CrossRefPubMed

146.

Recasens A, Carballo-Carbajal I, Parent A, Bove J, Gelpi E, Tolosa E et al (2018) Lack of pathogenic potential of peripheral alpha-synuclein aggregates from Parkinson’s disease patients. Acta Neuropathol Commun 6:8. https://doi.org/10.1186/s40478-018-0509-1 CrossRefPubMedPubMedCentral

147.

Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A et al (2014) Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362. https://doi.org/10.1002/ana.24066 CrossRefPubMed

148.

Regev A, Teichmann SA, Lander ES, Amit I, Benoist C, Birney E et al (2017) The human cell atlas. Elife 6:e27041. https://doi.org/10.7554/elife.27041 CrossRefPubMedPubMedCentral

149.

Ren Y, Liu W, Jiang H, Jiang Q, Feng J (2005) Selective vulnerability of dopaminergic neurons to microtubule depolymerization. J Biol Chem 280:34105–34112. https://doi.org/10.1074/jbc.M503483200 CrossRefPubMed

150.

Roberts RF, Wade-Martins R, Alegre-Abarrategui J (2015) Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain. Brain 138:1642–1657. https://doi.org/10.1093/brain/awv040 CrossRefPubMedPubMedCentral

151.

Rokad D, Ghaisas S, Harischandra DS, Jin H, Anantharam V, Kanthasamy A et al (2017) Role of neurotoxicants and traumatic brain injury in alpha-synuclein protein misfolding and aggregation. Brain Res Bull 133:60–70. https://doi.org/10.1016/j.brainresbull.2016.12.003 CrossRefPubMed

152.

Ronzitti G, Bucci G, Emanuele M, Leo D, Sotnikova TD, Mus LV et al (2014) Exogenous alpha-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release. J Neurosci 34:10603–10615. https://doi.org/10.1523/JNEUROSCI.0608-14.2014 CrossRefPubMedPubMedCentral

153.

Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE et al (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167:1469–1480.e1412. https://doi.org/10.1016/j.cell.2016.11.018 CrossRefPubMedPubMedCentral

154.

Sanchez-Martinez A, Beavan M, Gegg ME, Chau K-Y, Whitworth AJ, Schapira AHV (2016) Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Sci Rep 6:31380. https://doi.org/10.1038/srep31380 CrossRefPubMedPubMedCentral

155.

Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M (2017) Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol Sci 38:541–555. https://doi.org/10.1016/j.tips.2017.03.010 CrossRefPubMed

156.

Schneider SA, Alcalay RN (2017) Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov Disord 32:1504–1523. https://doi.org/10.1002/mds.27193 CrossRefPubMedPubMedCentral

157.

Schultz W (2007) Behavioral dopamine signals. Trends Neurosci 30:203–210. https://doi.org/10.1016/j.tins.2007.03.007 CrossRefPubMed

158.

Shrivastava AN, Redeker V, Fritz N, Pieri L, Almeida LG, Spolidoro M et al (2015) alpha-synuclein assemblies sequester neuronal alpha3-Na⁺/K⁺-ATPase and impair Na⁺ gradient. EMBO J 34:2408–2423. https://doi.org/10.15252/embj.201591397 CrossRefPubMedPubMedCentral

159.

Si K, Choi Y-B, White-Grindley E, Majumdar A, Kandel ER (2010) Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 140:421–435. https://doi.org/10.1016/j.cell.2010.01.008 CrossRefPubMed

160.

Si K, Kandel ER (2016) The role of functional prion-like proteins in the persistence of memory. Cold Spring Harb Perspect Biol 8:a021774. https://doi.org/10.1101/cshperspect.a021774 CrossRefPubMedPubMedCentral

161.

Simunovic F, Yi M, Wang Y, Macey L, Brown LT, Krichevsky AM et al (2009) Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson’s disease pathology. Brain 132:1795–1809. https://doi.org/10.1093/brain/awn323 CrossRefPubMed

162.

Spillantini MG, Goedert M (2000) The alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci 920:16–27CrossRefPubMed

163.

Subramaniam M, Althof D, Gispert S, Schwenk J, Auburger G, Kulik A et al (2014) Mutant alpha-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. J Neurosci 34:13586–13599. https://doi.org/10.1523/JNEUROSCI.5069-13.2014 CrossRefPubMedPubMedCentral

164.

Surmeier DJ (2018) Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J 285:3657–3668. https://doi.org/10.1111/febs.14607 CrossRefPubMedPubMedCentral

165.

Surmeier DJ, Obeso JA, Halliday GM (2017) Parkinson’s disease is not simply a prion disorder. J Neurosci 37:9799–9807. https://doi.org/10.1523/JNEUROSCI.1787-16.2017 CrossRefPubMedPubMedCentral

166.

Takanashi M, Funayama M, Matsuura E, Yoshino H, Li Y, Tsuyama S et al (2018) Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 pR1441H homozygous and heterozygous mutations. Acta Neuropathol Commun 6:105. https://doi.org/10.1186/s40478-018-0617-y CrossRefPubMedPubMedCentral

167.

Taylor TN, Potgieter D, Anwar S, Senior SL, Janezic S, Threlfell S et al (2014) Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P alpha-synuclein BAC transgenic mouse. Neurobiol Dis 62:193–207. https://doi.org/10.1016/j.nbd.2013.10.005 CrossRefPubMedPubMedCentral

168.

Tranah GJ, Blackwell T, Stone KL, Ancoli-Israel S, Paudel ML, Ensrud KE et al (2011) Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol 70:722–732. https://doi.org/10.1002/ana.22468 CrossRefPubMedPubMedCentral

169.

Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44:415–422. https://doi.org/10.1002/ana.410440324 CrossRefPubMed

170.

Unal CT, Golowasch JP, Zaborszky L (2012) Adult mouse basal forebrain harbors two distinct cholinergic populations defined by their electrophysiology. Front Behav Neurosci 6:21. https://doi.org/10.3389/fnbeh.2012.00021 CrossRefPubMedPubMedCentral

171.

Uryu K, Chen XH, Martinez D, Browne KD, Johnson VE, Graham DI et al (2007) Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 208:185–192. https://doi.org/10.1016/j.expneurol.2007.06.018 CrossRefPubMedPubMedCentral

172.

Valensin D, Dell’Acqua S, Kozlowski H, Casella L (2016) Coordination and redox properties of copper interaction with alpha-synuclein. J Inorg Biochem 163:292–300. https://doi.org/10.1016/j.jinorgbio.2016.04.012 CrossRefPubMed

173.

Valera E, Masliah E (2018) The neuropathology of multiple system atrophy and its therapeutic implications. Auton Neurosci 211:1–6. https://doi.org/10.1016/j.autneu.2017.11.002 CrossRefPubMed

174.

Vicario M, Cieri D, Brini M, Cali T (2018) The close encounter between alpha-synuclein and mitochondria. Front Neurosci 12:388. https://doi.org/10.3389/fnins.2018.00388 CrossRefPubMedPubMedCentral

175.

Vieira BD, Radford RA, Chung RS, Guillemin GJ, Pountney DL (2015) Neuroinflammation in multiple system atrophy: response to and cause of alpha-synuclein aggregation. Front Cell Neurosci 9:437. https://doi.org/10.3389/fncel.2015.00437 CrossRefPubMedPubMedCentral

176.

Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729CrossRefPubMed

177.

Villar-Pique A, Lopes da Fonseca T, Sant’Anna R, Szego EM, Fonseca-Ornelas L, Pinho R et al (2016) Environmental and genetic factors support the dissociation between alpha-synuclein aggregation and toxicity. Proc Natl Acad Sci USA 113:E6506–E6515. https://doi.org/10.1073/pnas.1606791113 CrossRefPubMedPubMedCentral

178.

Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71. https://doi.org/10.1016/j.neuron.2011.08.033 CrossRefPubMedPubMedCentral

179.

Voutsinas GE, Stavrou EF, Karousos G, Dasoula A, Papachatzopoulou A, Syrrou M et al (2010) Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease. Hum Mutat 31:685–691. https://doi.org/10.1002/humu.21248 CrossRefPubMed

180.

Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20CrossRefPubMed

181.

Wan W, Jin L, Wang Z, Wang L, Fei G, Ye F et al (2017) Iron deposition leads to neuronal alpha-synuclein pathology by inducing autophagy dysfunction. Front Neurol 8:1. https://doi.org/10.3389/fneur.2017.00001 CrossRefPubMedPubMedCentral

182.

Wang L, Das U, Scott DA, Tang Y, McLean PJ, Roy S (2014) Alpha-synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr Biol 24:2319–2326. https://doi.org/10.1016/j.cub.2014.08.027 CrossRefPubMedPubMedCentral

183.

Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM et al (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110:19555–19560. https://doi.org/10.1073/pnas.1318268110 CrossRefPubMedPubMedCentral

184.

Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA et al (2010) Alpha-synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190:1023–1037. https://doi.org/10.1083/jcb.201003122 CrossRefPubMedPubMedCentral

185.

Woerman AL, Kazmi SA, Patel S, Aoyagi A, Oehler A, Widjaja K et al (2018) Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci USA 115:409–414. https://doi.org/10.1073/pnas.1719369115 CrossRefPubMed

186.

Xiao Y, Chen X, Huang S, Li G, Mo M, Zhang L et al (2018) Iron promotes alpha-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome–lysosome fusion. J Neurochem 145:34–50. https://doi.org/10.1111/jnc.14312 CrossRefPubMed

187.

Xilouri M, Brekk OR, Stefanis L (2016) Autophagy and alpha-synuclein: relevance to Parkinson’s disease and related synucleopathies. Mov Disord 31:178–192. https://doi.org/10.1002/mds.26477 CrossRefPubMed

188.

Yamada K, Iwatsubo T (2018) Extracellular alpha-synuclein levels are regulated by neuronal activity. Mol Neurodegener 13:9. https://doi.org/10.1186/s13024-018-0241-0 CrossRefPubMedPubMedCentral

189.

Yang Y, Shepherd C, Halliday G (2015) Aneuploidy in Lewy body diseases. Neurobiol Aging 36:1253–1260. https://doi.org/10.1016/j.neurobiolaging.2014.12.016 CrossRefPubMed

190.

Yuan YH, Yan WF, Sun JD, Huang JY, Mu Z, Chen NH (2015) The molecular mechanism of rotenone-induced alpha-synuclein aggregation: emphasizing the role of the calcium/GSK3beta pathway. Toxicol Lett 233:163–171. https://doi.org/10.1016/j.toxlet.2014.11.029 CrossRefPubMed

191.

Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I et al (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173. https://doi.org/10.1002/ana.10795 CrossRefPubMed

Title: Selective vulnerability in α-synucleinopathies
Authors: Javier Alegre-Abarrategui
Katherine R. Brimblecombe
Rosalind F. Roberts
Elisavet Velentza-Almpani
Bension S. Tilley
Nora Bengoa-Vergniory
Christos Proukakis
Publication date: 01-11-2019
Publisher: Springer Berlin Heidelberg
Keywords: Pathology
Parkinson's Disease
Published in: Acta Neuropathologica / Issue 5/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02010-2

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Selective vulnerability in α-synucleinopathies

Abstract

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Abstract

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