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Published in:

Open Access 01-10-2014 | Review

Alpha-synuclein biology in Lewy body diseases

Authors: Woojin Scott Kim, Katarina Kågedal, Glenda M Halliday

Published in: Alzheimer's Research & Therapy | Issue 5-8/2014

Abstract

α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein intracellularly. Primary α-synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, with α-synuclein also found secondarily in a number of other diseases, including Alzheimer's disease. Understanding how α-synuclein aggregates form in these different disorders is important for the understanding of its pathogenesis in Lewy body diseases. PD is the most prevalent of the α-synucleinopathies and much of the initial research on α-synuclein Lewy body pathology was based on PD but is also relevant to Lewy bodies in other diseases (dementia with Lewy bodies and Alzheimer's disease). Polymorphism and mutation studies of SNCA, the gene that encodes α-synuclein, provide much evidence for a causal link between α-synuclein and PD. Among the primary α-synucleinopathies, multiple system atrophy is unique in that α-synuclein deposition occurs in oligodendrocytes rather than neurons. It is unclear whether α-synuclein originates from oligodendrocytes or whether it is transmitted somehow from neurons. α-Synuclein exists as a natively unfolded monomer in the cytosol, but in the presence of lipid membranes it is thought to undergo a conformational change to a folded α-helical secondary structure that is prone to forming dimers and oligomers. Posttranslational modification of α-synuclein, such as phosphorylation, ubiquitination and nitration, has been widely implicated in α-synuclein aggregation process and neurotoxicity. Recent studies using animal and cell models, as well as autopsy studies of patients with neuron transplants, provided compelling evidence for prion-like propagation of α-synuclein. This observation has implications for therapeutic strategies, and much recent effort is focused on developing antibodies that target extracellular α-synuclein.

Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T: Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993, 90: 11282-11286.PubMedCentral

Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM, Iwatsubo T, Trojanowski JQ: Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998, 153: 1365-1370.PubMedCentral

Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y: Alpha-synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation. Brain Res. 2001, 888: 287-296.

Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature. 1997, 388: 839-840.

Gai WP, Power JH, Blumbergs PC, Blessing WW: Multiple-system atrophy: a new alpha-synuclein disease?. Lancet. 1998, 352: 547-548.

Newell KL, Boyer P, Gomez-Tortosa E, Hobbs W, Hedley-Whyte ET, Vonsattel JP, Hyman BT: Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury. J Neuropathol Exp Neurol. 1999, 58: 1263-1268.

Wolozin B, Behl C: Mechanisms of neurodegenerative disorders: part 1: protein aggregates. Arch Neurol. 2000, 57: 793-796.

Lashuel HA, Overk CR, Oueslati A, Masliah E: The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013, 14: 38-48.PubMedCentral

Beyer K: Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol. 2006, 112: 237-251.

10.

Clayton DF, George JM: The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 1998, 21: 249-254.

11.

Pals P, Lincoln S, Manning J, Heckman M, Skipper L, Hulihan M, Van den Broeck M, De Pooter T, Cras P, Crook J, Van Broeckhoven C, Farrer MJ: alpha-Synuclein promoter confers susceptibility to Parkinson's disease. Ann Neurol. 2004, 56: 591-595.

12.

Rajput A, Vilarino-Guell C, Rajput ML, Ross OA, Soto-Ortolaza AI, Lincoln SJ, Cobb SA, Heckman MG, Farrer MJ: Alpha-synuclein polymorphisms are associated with Parkinson's disease in a Saskatchewan population. Mov Disord. 2009, 24: 2411-2414.

13.

Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, Doheny KF, Gusella JF, Nichols WC, Foroud T, Myers RH: Genome-wide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet. 2009, 124: 593-605.PubMedCentral

14.

Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C: Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA. 2006, 296: 661-670.

15.

Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997, 276: 2045-2047.

16.

Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998, 18: 106-108.

17.

Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004, 55: 164-173.

18.

Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL, Houlden H, Schapira AH: A novel alpha-synuclein missense mutation in Parkinson disease. Neurology. 2013, 80: 1062-1064.PubMedCentral

19.

Lesage S, Anheim M, Letournel F, Bousset L, Honore A, Rozas N, Pieri L, Madiona K, Durr A, Melki R, Verny C, Brice A: G51D alpha-synuclein mutation causes a novel Parkinsonian-pyramidal syndrome. Ann Neurol. 2013, 73: 459-471.

20.

Conway KA, Harper JD, Lansbury PT: Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med. 1998, 4: 1318-1320.

21.

Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K: alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003, 302: 841-

22.

Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destee A: Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet. 2004, 364: 1167-1169.

23.

Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A: Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet. 2004, 364: 1169-1171.

24.

Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson EM, Schule B, Langston JW, Middleton FA, Ross OA, Hulihan M, Gasser T, Farrer MJ: Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology. 2007, 68: 916-922.

25.

Nishioka K, Ross OA, Ishii K, Kachergus JM, Ishiwata K, Kitagawa M, Kono S, Obi T, Mizoguchi K, Inoue Y, Imai H, Takanashi M, Mizuno Y, Farrer MJ, Hattori N: Expanding the clinical phenotype of SNCA duplication carriers. Mov Disord. 2009, 24: 1811-1819.

26.

Murphy DD, Rueter SM, Trojanowski JQ, Lee VM: Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000, 20: 3214-3220.

27.

Bonini NM, Giasson BI: Snaring the function of alpha-synuclein. Cell. 2005, 123: 359-361.

28.

Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC: Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010, 329: 1663-1667.PubMedCentral

29.

Kokhan VS, Afanasyeva MA, Van'kin GI: alpha-Synuclein knockout mice have cognitive impairments. Behav Brain Res. 2012, 231: 226-230.

30.

Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, Meijer L, Kahle PJ, Haass C: Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein. J Biol Chem. 2000, 275: 390-397.

31.

Nakamura T, Yamashita H, Takahashi T, Nakamura S: Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem Biophys Res Commun. 2001, 280: 1085-1092.

32.

Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ: Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006, 281: 29739-29752.

33.

Nonaka T, Iwatsubo T, Hasegawa M: Ubiquitination of alpha-synuclein. Biochemistry. 2005, 44: 361-368.

34.

House CM, Hancock NC, Moller A, Cromer BA, Fedorov V, Bowtell DD, Parker MW, Polekhina G: Elucidation of the substrate binding site of Siah ubiquitin ligase. Structure. 2006, 14: 695-701.

35.

Lee JT, Wheeler TC, Li L, Chin LS: Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet. 2008, 17: 906-917.

36.

Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM: Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000, 290: 985-989.

37.

Liu Y, Qiang M, Wei Y, He R: A novel molecular mechanism for nitrated α-synuclein-induced cell death. J Mol Cell Biol. 2011, 3: 239-249.

38.

Danielson SR, Held JM, Schilling B, Oo M, Gibson BW, Andersen JK: Preferentially increased nitration of alpha-synuclein at tyrosine-39 in a cellular oxidative model of Parkinson's disease. Anal Chem. 2009, 81: 7823-7828.PubMedCentral

39.

Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW: Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 2008, 14: 504-506.

40.

Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P: Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008, 14: 501-503.

41.

Brundin P, Melki R, Kopito R: Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010, 11: 301-307.PubMedCentral

42.

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

43.

Braak H, Rub U, Gai WP, Del Tredici K: Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003, 110: 517-536.

44.

Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P: alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011, 121: 715-725.PubMedCentral

45.

Ulusoy A, Rusconi R, Perez-Revuelta BI, Musgrove RE, Helwig M, Winzen-Reichert B, Di Monte DA: Caudo-rostral brain spreading of alpha-synuclein through vagal connections. EMBO Mol Med. 2013, 5: 1051-1059.PubMedCentral

46.

Rey NL, Petit GH, Bousset L, Melki R, Brundin P: Transfer of human alpha-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol. 2013, 126: 555-573.PubMedCentral

47.

Luk KC, Lee VM: Modeling Lewy pathology propagation in Parkinson's disease. Parkinsonism Relat Disord. 2014, 20: S85-S87.PubMedCentral

48.

Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, Fernagut PO, Blesa J, Parent A, Perier C, Farinas I, Obeso JA, Bezard E, Vila M: Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol. 2014, 75: 351-362.

49.

Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, Mann DM, Hasegawa M: Prion-like spreading of pathological alpha-synuclein in brain. Brain. 2013, 136: 1128-1138.PubMedCentral

50.

Kretzschmar H, Tatzelt J: Prion disease: a tale of folds and strains. Brain Pathol. 2013, 23: 321-332.

51.

Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, Habenstein B, Madiona K, Olieric V, Bockmann A, Meier BH, Melki R: Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013, 4: 2575-PubMedCentral

52.

Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM: Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013, 154: 103-117.

53.

Narkiewicz J, Giachin G, Legname G: In vitro aggregation assays for the characterization of alpha-synuclein prion-like properties. Prion. 2014, 8: 19-32.PubMedCentral

54.

Halliday GM, Holton JL, Revesz T, Dickson DW: Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011, 122: 187-204.

55.

Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M: alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci U S A. 1998, 95: 6469-6473.PubMedCentral

56.

Leng Y, Chase TN, Bennett MC: Muscarinic receptor stimulation induces translocation of an alpha-synuclein oligomer from plasma membrane to a light vesicle fraction in cytoplasm. J Biol Chem. 2001, 276: 28212-28218.

57.

Davidson WS, Jonas A, Clayton DF, George JM: Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem. 1998, 273: 9443-9449.

58.

Segrest JP, Jones MK, De Loof H, Brouillette CG, Venkatachalapathi YV, Anantharamaiah GM: The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. J Lipid Res. 1992, 33: 141-166.

59.

Cole NB, Murphy DD, Grider T, Rueter S, Brasaemle D, Nussbaum RL: Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. J Biol Chem. 2002, 277: 6344-6352.

60.

Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH: Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci. 2004, 24: 6715-6723.

61.

Bartels T, Choi JG, Selkoe DJ: alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011, 477: 107-110.PubMedCentral

62.

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A: Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005, 65: 1863-1872.

63.

Weisman D, Cho M, Taylor C, Adame A, Thal LJ, Hansen LA: In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution. Neurology. 2007, 69: 356-359.

64.

Fujishiro H, Ferman TJ, Boeve BF, Smith GE, Graff-Radford NR, Uitti RJ, Wszolek ZK, Knopman DS, Petersen RC, Parisi JE, Dickson DW: Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases. J Neuropathol Exp Neurol. 2008, 67: 649-656.PubMedCentral

65.

Oinas M, Polvikoski T, Sulkava R, Myllykangas L, Juva K, Notkola IL, Rastas S, Niinisto L, Kalimo H, Paetau A: Neuropathologic findings of dementia with lewy bodies (DLB) in a population-based Vantaa 85+ study. J Alzheimers Dis. 2009, 18: 677-689.

66.

Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince PG, Perry R, McKeith I, Katona CL: Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy. J Neurol Neurosurg Psychiatry. 2007, 78: 1176-1181.PubMedCentral

67.

Nelson PT, Jicha GA, Kryscio RJ, Abner EL, Schmitt FA, Cooper G, Xu LO, Smith CD, Markesbery WR: Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J Neurol. 2010, 257: 359-366.PubMedCentral

68.

Ferman TJ, Boeve BF, Smith GE, Lin SC, Silber MH, Pedraza O, Wszolek Z, Graff-Radford NR, Uitti R, Van Gerpen J, Pao W, Knopman D, Pankratz VS, Kantarci K, Boot B, Parisi JE, Dugger BN, Fujishiro H, Petersen RC, Dickson DW: Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology. 2011, 77: 875-882.PubMedCentral

69.

Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I: Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 2009, 8: 1150-1157.

70.

Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S, Ferrer I, Gelpi E, Kovari V, Kretzschmar H, Nagy Z, Parchi P, Seilhean D, Soininen H, Troakes C, Budka H: Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord. 2008, 26: 343-350.

71.

Ballard C, Ziabreva I, Perry R, Larsen JP, O'Brien J, McKeith I, Perry E, Aarsland D: Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology. 2006, 67: 1931-1934.

72.

Tiraboschi P, Hansen LA, Alford M, Sabbagh MN, Schoos B, Masliah E, Thal LJ, Corey-Bloom J: Cholinergic dysfunction in diseases with Lewy bodies. Neurology. 2000, 54: 407-411.

73.

Shimada H, Hirano S, Shinotoh H, Aotsuka A, Sato K, Tanaka N, Ota T, Asahina M, Fukushi K, Kuwabara S, Hattori T, Suhara T, Irie T: Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology. 2009, 73: 273-278.

74.

Marcone A, Garibotto V, Moresco RM, Florea I, Panzacchi A, Carpinelli A, Virta JR, Tettamanti M, Borroni B, Padovani A, Bertoldo A, Herholz K, Rinne JO, Cappa SF, Perani D: [11C]-MP4A PET cholinergic measurements in amnestic mild cognitive impairment, probable Alzheimer's disease, and dementia with Lewy bodies: a Bayesian method and voxel-based analysis. J Alzheimers Dis. 2012, 31: 387-399.

75.

Laske C, Fallgatter AJ, Stransky E, Hagen K, Berg D, Maetzler W: Decreased alpha-synuclein serum levels in patients with Lewy body dementia compared to Alzheimer's disease patients and control subjects. Dement Geriatr Cogn Disord. 2011, 31: 413-416.

76.

Gelb DJ, Oliver E, Gilman S: Diagnostic criteria for Parkinson disease. Arch Neurol. 1999, 56: 33-39.

77.

Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B: Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord. 2007, 22: 1689-1707.

78.

Irwin DJ, Lee VM, Trojanowski JQ: Parkinson's disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat Rev Neurosci. 2013, 14: 626-636.PubMedCentral

79.

Zhou J, Broe M, Huang Y, Anderson JP, Gai WP, Milward EA, Porritt M, Howells D, Hughes AJ, Wang X, Halliday GM: Changes in the solubility and phosphorylation of alpha-synuclein over the course of Parkinson's disease. Acta Neuropathol. 2011, 121: 695-704.

80.

Lue LF, Walker DG, Adler CH, Shill H, Tran H, Akiyama H, Sue LI, Caviness J, Sabbagh MN, Beach TG: Biochemical increase in phosphorylated alpha-synuclein precedes histopathology of Lewy-type synucleinopathies. Brain Pathol. 2012, 22: 745-756.PubMedCentral

81.

Walker DG, Lue LF, Adler CH, Shill HA, Caviness JN, Sabbagh MN, Akiyama H, Serrano GE, Sue LI, Beach TG: Changes in properties of serine 129 phosphorylated alpha-synuclein with progression of Lewy-type histopathology in human brains. Exp Neurol. 2013, 240: 190-204.PubMedCentral

82.

Tong J, Wong H, Guttman M, Ang LC, Forno LS, Shimadzu M, Rajput AH, Muenter MD, Kish SJ, Hornykiewicz O, Furukawa Y: Brain alpha-synuclein accumulation in multiple system atrophy, Parkinson's disease and progressive supranuclear palsy: a comparative investigation. Brain. 2010, 133: 172-188.

83.

Halliday G, Hely M, Reid W, Morris J: The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol. 2008, 115: 409-415.

84.

Wenning G, Tison F, Ben Shlomo Y, Daniel S, Quinn N: Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. 1997, 12: 133-147.

85.

Ozawa T, Okuizumi K, Ikeuchi T, Wakabayashi K, Takahashi H, Tsuji S: Analysis of the expression level of alpha-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy. Acta Neuropathol. 2001, 102: 188-190.

86.

Baker KG, Huang Y, McCann H, Gai WP, Jensen PH, Halliday GM: P25alpha immunoreactive but alpha-synuclein immunonegative neuronal inclusions in multiple system atrophy. Acta Neuropathol. 2006, 111: 193-195.

87.

Huang Y, Song YJ, Murphy K, Holton JL, Lashley T, Revesz T, Gai WP, Halliday GM: LRRK2 and parkin immunoreactivity in multiple system atrophy inclusions. Acta Neuropathol. 2008, 116: 639-646.

88.

Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, Hojrup P, Otzen D, Halliday GM, Jensen PH: p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol. 2007, 171: 1291-1303.PubMedCentral

89.

Jin H, Ishikawa K, Tsunemi T, Ishiguro T, Amino T, Mizusawa H: Analyses of copy number and mRNA expression level of the alpha-synuclein gene in multiple system atrophy. J Med Dental Sci. 2008, 55: 145-153.

90.

Morris HR, Vaughan JR, Datta SR, Bandopadhyay R, Rohan De Silva HA, Schrag A, Cairns NJ, Burn D, Nath U, Lantos PL, Daniel S, Lees AJ, Quinn NP, Wood NW: Multiple system atrophy/progressive supranuclear palsy: alpha-synuclein, synphilin, tau, and APOE. Neurology. 2000, 55: 1918-1920.

91.

Ozawa T, Takano H, Onodera O, Kobayashi H, Ikeuchi T, Koide R, Okuizumi K, Shimohata T, Wakabayashi K, Takahashi H, Tsuji S: No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy. Neurosci Lett. 1999, 270: 110-112.

92.

Al-Chalabi A, Durr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, Leigh PN, Bensimon G: Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS One. 2009, 4: e7114-PubMedCentral

93.

Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J, Paisan-Ruiz C, Bras J, Ding J, Chen H, Traynor BJ, Arepalli S, Zonozi RR, Revesz T, Holton J, Wood N, Lees A, Oertel W, Wullner U, Goldwurm S, Pellecchia MT, Illig T, Riess O, Fernandez HH, Rodriguez RL, Okun M: SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009, 65: 610-614.PubMedCentral

94.

Stemberger S, Scholz SW, Singleton AB, Wenning GK: Genetic players in multiple system atrophy: unfolding the nature of the beast. Neurobiol Aging. 1924, 2011: e5-e14.

95.

Sailer A: First genome-wide association study in multiple system atrophy. Mov Disord. 2012, 27: 1425-

96.

Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, Wenning GK: Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol. 2005, 166: 869-876.PubMedCentral

97.

Miller DW, Johnson JM, Solano SM, Hollingsworth ZR, Standaert DG, Young AB: Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm. 2005, 112: 1613-1624.

98.

Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K: Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol. 2002, 176: 98-104.

99.

Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM: alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res. 2000, 62: 9-14.

100.

Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C: Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 2002, 3: 583-588.PubMedCentral

101.

Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski JQ, Lee VM: Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005, 45: 847-859.

102.

Lee HJ, Suk JE, Bae EJ, Lee SJ: Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun. 2008, 372: 423-428.

103.

Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ: Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010, 285: 9262-9272.PubMedCentral

104.

Toledo JB, Cairns NJ, Da X, Chen K, Carter D, Fleisher A, Householder E, Ayutyanont N, Roontiva A, Bauer RJ, Eisen P, Shaw LM, Davatzikos C, Weiner MW, Reiman EM, Morris JC, Trojanowski JQ: Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol Commun. 2013, 1: 65-PubMedCentral

105.

Mikolaenko I, Pletnikova O, Kawas CH, O'Brien R, Resnick SM, Crain B, Troncoso JC: Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA). J Neuropathol Exp Neurol. 2005, 64: 156-162.

106.

Hamilton RL: Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000, 10: 378-384.

107.

Iseki E: Dementia with Lewy bodies: reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease. Neuropathology. 2004, 24: 72-78.

108.

Marui W, Iseki E, Ueda K, Kosaka K: Occurrence of human alpha-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer's disease. J Neurol Sci. 2000, 174: 81-84.

109.

Compta Y, Parkkinen L, O'Sullivan SS, Vandrovcova J, Holton JL, Collins C, Lashley T, Kallis C, Williams DR, de Silva R, Lees AJ, Revesz T: Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?. Brain. 2011, 134: 1493-1505.PubMedCentral

110.

Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, Giannakopoulos P: Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson's disease. Acta Neuropathol. 2003, 106: 83-88.

111.

Jellinger KA, Seppi K, Wenning GK, Poewe W: Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J Neural Transm. 2002, 109: 329-339.

112.

Irwin DJ, White MT, Toledo JB, Xie SX, Robinson JL, Van Deerlin V, Lee VM, Leverenz JB, Montine TJ, Duda JE, Hurtig HI, Trojanowski JQ: Neuropathologic substrates of Parkinson disease dementia. Ann Neurol. 2012, 72: 587-598.PubMedCentral

113.

Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM: Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010, 30: 7281-7289.PubMedCentral

114.

Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM: Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron. 2002, 34: 521-533.

115.

Rolinski M, Fox C, Maidment I, McShane R: Cholinesterase inhibitors for dementia with Lewy bodies. Parkinson's disease dementia and cognitive impairment in Parkinson's disease. Cochrane Database Syst Rev. 2012, 3: CD006504-

116.

Ballard CG, Chalmers KA, Todd C, McKeith IG, O'Brien JT, Wilcock G, Love S, Perry EK: Cholinesterase inhibitors reduce cortical Abeta in dementia with Lewy bodies. Neurology. 2007, 68: 1726-1729.

117.

Vekrellis K, Stefanis L: Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson's disease and other synucleinopathies. Expert Opin Ther Targets. 2012, 16: 421-432.

118.

Lee HJ, Bae EJ, Lee SJ: Extracellular alpha-synuclein - a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014, 10: 92-98.

119.

Marchiani A, Mammi S, Siligardi G, Hussain R, Tessari I, Bubacco L, Delogu G, Fabbri D, Dettori MA, Sanna D, Dedola S, Serra PA, Ruzza P: Small molecules interacting with alpha-synuclein: antiaggregating and cytoprotective properties. Amino Acids. 2013, 45: 327-338.

120.

Moloney TC, Hyland R, O'Toole D, Paucard A, Kirik D, O'Doherty A, Gorman AM, Dowd E: Heat shock protein 70 reduces alpha-synuclein-induced predegenerative neuronal dystrophy in the alpha-synuclein viral gene transfer rat model of Parkinson's disease. CNS Neurosci Ther. 2014, 20: 50-58.

121.

Putcha P, Danzer KM, Kranich LR, Scott A, Silinski M, Mabbett S, Hicks CD, Veal JM, Steed PM, Hyman BT, McLean PJ: Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity. J Pharmacol Exp Ther. 2010, 332: 849-857.PubMedCentral

122.

Toth G, Gardai SJ, Zago W, Bertoncini CW, Cremades N, Roy SL, Tambe MA, Rochet JC, Galvagnion C, Skibinski G, Finkbeiner S, Bova M, Regnstrom K, Chiou SS, Johnston J, Callaway K, Anderson JP, Jobling MF, Buell AK, Yednock TA, Knowles TP, Vendruscolo M, Christodoulou J, Dobson CM, Schenk D, McConlogue L: Targeting the intrinsically disordered structural ensemble of alpha-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease. PLoS One. 2014, 9: e87133-PubMedCentral

123.

Jones DR, Moussaud S, McLean P: Targeting heat shock proteins to modulate alpha-synuclein toxicity. Ther Adv Neurol Disord. 2014, 7: 33-51.PubMedCentral

124.

Sinha G: Roche bets on alpha-synuclein for Parkinson's. Nat Biotechnol. 2014, 32: 212-

125.

Valera E, Masliah E: Immunotherapy for neurodegenerative diseases: focus on alpha-synucleinopathies. Pharmacol Ther. 2013, 138: 311-322.PubMedCentral

126.

Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, Santic R, Meindl S, Vigl B, Smrzka O, Schneeberger A, Mattner F, Masliah E: Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 2014, 127: 861-879.PubMedCentral

127.

Lindstrom V, Ihse E, Fagerqvist T, Bergstrom J, Nordstrom E, Moller C, Lannfelt L, Ingelsson M: Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders. Immunotherapy. 2014, 6: 141-153.

128.

Ruzza P, Siligardi G, Hussain R, Marchiani A, Islami M, Bubacco L, Delogu G, Fabbri D, Dettori MA, Sechi M, Pala N, Spissu Y, Migheli R, Serra PA, Sechi G: Ceftriaxone blocks the polymerization of alpha-synuclein and exerts neuroprotective effects in vitro. ACS Chem Neurosci. 2014, 5: 30-38.PubMedCentral

129.

Low PA, Robertson D, Gilman S, Kaufmann H, Singer W, Biaggioni I, Freeman R, Perlman S, Hauser RA, Cheshire W, Lessig S, Vernino S, Mandrekar J, Dupont WD, Chelimsky T, Galpern WR: Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014, 13: 268-275.PubMedCentral

Title: Alpha-synuclein biology in Lewy body diseases
Authors: Woojin Scott Kim
Katarina Kågedal
Glenda M Halliday
Publication date: 01-10-2014
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 5-8/2014
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-014-0073-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Alpha-synuclein biology in Lewy body diseases

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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