Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation

J Biol Chem. 1999 Apr 2;274(14):9843-6. doi: 10.1074/jbc.274.14.9843.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major component of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiological temperature in vitro. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for the A53T mutant protein. These data suggest that the formation of alpha-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations.

MeSH terms

  • Cell Line
  • Circular Dichroism
  • Cloning, Molecular
  • Humans
  • Mutation*
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics*
  • Parkinson Disease / genetics*
  • Phosphoproteins / chemistry*
  • Phosphoproteins / genetics*
  • Protein Conformation
  • Protein Structure, Secondary
  • Spectroscopy, Fourier Transform Infrared
  • Synucleins
  • alpha-Synuclein

Substances

  • Nerve Tissue Proteins
  • Phosphoproteins
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein