title: Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations.
abstract: Abnormal biology of alpha-synuclein (alpha-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other alpha-synucleinopathies. Herein, we demonstrate that C-terminally truncated alpha-Syn (alpha-SynDeltaC), enriched in the pathological alpha-Syn aggregates, is normally generated from full-length alpha-Syn independent of alpha-Syn aggregation in brains and in cultured cells. The accumulation of alpha-SynDeltaC is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant alpha-Syn is associated with the enhanced cellular accumulation of alpha-SynDeltaC. Moreover, substoichiometric amounts of alpha-SynDeltaC enhance the in vitro aggregation of the more abundant full-length alpha-Syn. Finally, cases of alpha-synucleinopathy exhibit increases in the total soluble alpha-Syn and a higher proportion of soluble alpha-SynDeltaC, a condition favoring the aggregation of alpha-Syn. Collectively, our results indicate that the biology behind the generation and accumulation of alpha-SynDeltaC is likely to have relevance for the initiation and the progression of alpha-Syn aggregation in vivo.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Wenxue
authors.initials: W
authors.lastname: Li
authors.forename: Neva
authors.initials: N
authors.lastname: West
authors.forename: Emanuela
authors.initials: E
authors.lastname: Colla
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Laura
authors.initials: L
authors.lastname: Marsh
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Pekka
authors.initials: P
authors.lastname: Jäkälä
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.forename: Donald L
authors.initials: DL
authors.lastname: Price
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D018604:Epitope Mapping; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein