Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease

Nat Med. 1998 Nov;4(11):1318-20. doi: 10.1038/3311.


Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.

Publication types

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

MeSH terms

  • Age of Onset
  • Alanine
  • Amino Acid Substitution
  • Circular Dichroism
  • Humans
  • Lewy Bodies / pathology
  • Lewy Bodies / ultrastructure*
  • Microscopy, Atomic Force
  • Microscopy, Electron
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / ultrastructure
  • Neurons / pathology*
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Parkinson Disease / physiopathology
  • Phosphoproteins / genetics
  • Point Mutation*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / ultrastructure
  • Substantia Nigra / pathology
  • Synucleins
  • Threonine
  • alpha-Synuclein


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