α-Synuclein shares physical and functional homology with 14-3-3 proteins

Natalie Ostrerova, Leonard Petrucelli, Matthew Farrer, Nitinkumar Mehta, Peter Choi, John Hardy, Benjamin Wolozin

Research output: Contribution to journalArticle

432 Scopus citations

Abstract

α-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in α-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of α-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that α-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of α- synuclein and 14-3-3 proteins share over 40% homology. In addition, α- synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of α- synuclein inhibits protein kinase C activity. The association of α-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of α-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type α-synuclein is toxic, and overexpression of α-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of α-synuclein suggests that it might act as a protein chaperone and that accumulation of α-synuclein could contribute to cell death in neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)5782-5791
Number of pages10
JournalJournal of Neuroscience
Volume19
Issue number14
DOIs
StatePublished - Jul 15 1999

Keywords

  • 14-3-3 proteins
  • Alzheimer's disease
  • Apoptosis
  • BAD
  • Extracellular regulated kinase
  • Parkinson's disease
  • Protein kinase C
  • Synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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