Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations.
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.
Li
Wenxue
W
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
West
Neva
N
Colla
Emanuela
E
Pletnikova
Olga
O
Troncoso
Juan C
JC
Marsh
Laura
L
Dawson
Ted M
TM
Jäkälä
Pekka
P
Hartmann
Tobias
T
Price
Donald L
DL
Lee
Michael K
MK
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
D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein