Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

Wenxue Li, Neva West, Emanuela Colla, Olga Pletnikova, Juan C. Troncoso, Laura Marsh, Ted M. Dawson, Pekka Jäkälä, Tobias Hartmann, Donald L. Price, Michael K. Lee

Research output: Contribution to journalArticlepeer-review

305 Scopus citations

Abstract

Abnormal biology of α-synuclein (α-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other α-synucleinopathies. Herein, we demonstrate that C-terminally truncated α-Syn (α-SynΔC), enriched in the pathological α-Syn aggregates, is normally generated from full-length α-Syn independent of α-Syn aggregation in brains and in cultured cells. The accumulation of α-SynΔC is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant α-Syn is associated with the enhanced cellular accumulation of α-SynΔC Moreover, substoichiometric amounts of α-SynΔC enhance the in vitro aggregation of the more abundant full-length α-Syn. Finally, cases of a-synucleinopathy exhibit increases in the total soluble α-Syn and a higher proportion of soluble α-SynΔC, a condition favoring the aggregation of α-Syn. Collectively, our results indicate that the biology behind the generation and accumulation of α-SynΔC is likely to have relevance for the initiation and the progression of α-Syn aggregation in vivo.

Original languageEnglish (US)
Pages (from-to)2162-2167
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number6
DOIs
StatePublished - Feb 8 2005

Keywords

  • Lewy body
  • Mass spectrometry
  • Proteolysis
  • α-synucleinopathy

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