Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid

Biochemistry. 2000 Mar 14;39(10):2552-63. doi: 10.1021/bi991447r.


Two missense mutations in the gene encoding alpha-synuclein have been linked to rare, early-onset forms of Parkinson's disease (PD). These forms of PD, as well as the common idiopathic form, are characterized by the presence of cytoplasmic neuronal deposits, called Lewy bodies, in the affected region of the brain. Lewy bodies contain alpha-synuclein in a form that resembles fibrillar Abeta derived from Alzheimer's disease (AD) amyloid plaques. One of the mutant forms of alpha-synuclein (A53T) fibrillizes more rapidly in vitro than does the wild-type protein, suggesting that a correlation may exist between the rate of in vitro fibrillization and/or oligomerization and the progression of PD, analogous to the relationship between Abeta fibrillization in vitro and familial AD. In this paper, fibrils generated in vitro from alpha-synuclein, wild-type and both mutant forms, are shown to possess very similar features that are characteristic of amyloid fibrils, including a wound and predominantly unbranched morphology (demonstrated by atomic force and electron microscopies), distinctive dye-binding properties (Congo red and thioflavin T), and antiparallel beta-sheet structure (Fourier transform infrared spectroscopy and circular dichroism spectroscopy). alpha-Synuclein fibrils are relatively resistant to proteolysis, a property shared by fibrillar Abeta and the disease-associated fibrillar form of the prion protein. These data suggest that PD, like AD, is a brain amyloid disease that, unlike AD, is characterized by cytoplasmic amyloid (Lewy bodies). In addition to amyloid fibrils, a small oligomeric form of alpha-synuclein, which may be analogous to the Abeta protofibril, was observed prior to the appearance of fibrils. This species or a related one, rather than the fibril itself, may be responsible for neuronal death.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine / genetics
  • Amino Acid Sequence
  • Amyloid / chemistry
  • Amyloid / metabolism*
  • Amyloid / ultrastructure
  • Benzothiazoles
  • Binding Sites
  • Brain / metabolism
  • Brain / pathology
  • Brain / ultrastructure
  • Circular Dichroism
  • Congo Red
  • Endopeptidases / metabolism
  • Humans
  • Hydrolysis
  • Immunohistochemistry
  • Lewy Bodies / metabolism
  • Lewy Bodies / pathology
  • Lewy Bodies / ultrastructure
  • Microscopy, Atomic Force
  • Microscopy, Polarization
  • Molecular Sequence Data
  • Mutation, Missense*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / ultrastructure
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Postmortem Changes
  • Proline / genetics
  • Protein Structure, Secondary
  • Recombinant Proteins / biosynthesis
  • Spectrometry, Fluorescence
  • Spectroscopy, Fourier Transform Infrared
  • Synucleins
  • Thiazoles / metabolism
  • Threonine / genetics
  • alpha-Synuclein


  • Amyloid
  • Benzothiazoles
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • SNCA protein, human
  • Synucleins
  • Thiazoles
  • alpha-Synuclein
  • thioflavin T
  • Threonine
  • Congo Red
  • Proline
  • Endopeptidases
  • Alanine