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

J Neurosci. 1999 Jul 15;19(14):5782-91. doi: 10.1523/JNEUROSCI.19-14-05782.1999.

Abstract

alpha-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in alpha-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha-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 alpha-synuclein inhibits protein kinase C activity. The association of alpha-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of alpha-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type alpha-synuclein is toxic, and overexpression of alpha-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha-synuclein suggests that it might act as a protein chaperone and that accumulation of alpha-synuclein could contribute to cell death in neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Cell Line
  • Cloning, Molecular
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Gene Expression Regulation
  • Humans
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Point Mutation
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Synucleins
  • Transfection
  • Tyrosine 3-Monooxygenase*
  • alpha-Synuclein

Substances

  • 14-3-3 Proteins
  • Enzyme Inhibitors
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Proteins
  • Recombinant Proteins
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • Tyrosine 3-Monooxygenase
  • Protein Kinase C