Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation

Exp Neurol. 2004 Jun;187(2):279-88. doi: 10.1016/j.expneurol.2004.01.007.


Mutations in the alpha-synuclein (alpha-syn) gene are responsible for a rare familial parkinsonism syndrome, a finding that has led to extensive characterization of altered alpha-syn structure in sporadic Parkinson's disease (PD) and other neurodegenerative disorders. We report here the immunohistochemical, biochemical and ultrastructural characterization of alpha-syn neuropathology in a case of familial PD with the A53T alpha-syn gene mutation. Insoluble filamentous alpha-syn lesions were detected in almost all brain regions examined and as in sporadic PD, we observed the accumulation of insoluble nitrated alpha-syn in this familial disorder. Significant accumulations of filamentous insoluble tau protein also were detected in some brain regions of this patient, suggesting a role for A53T mutant alpha-syn in tau fibrillization. Indeed, in vitro studies of tau and alpha-syn fibrillization showed that the A53T mutation accelerated alpha-syn fibril formation, initiated tau assembly into filaments and synergistically enhanced fibrillization of both tau and alpha-syn. Our data implicate fibrillization of alpha-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases.

Publication types

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

MeSH terms

  • Amino Acid Substitution / genetics
  • Brain / metabolism
  • Brain / pathology
  • Brain / ultrastructure
  • Brain Chemistry
  • Disease Progression
  • Humans
  • Immunohistochemistry
  • Macromolecular Substances
  • Male
  • Middle Aged
  • Mutation / genetics
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Neurofibrillary Tangles / metabolism*
  • Neurofibrillary Tangles / pathology
  • Neurofibrillary Tangles / ultrastructure
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Solubility
  • Synucleins
  • alpha-Synuclein
  • tau Proteins / chemistry
  • tau Proteins / metabolism*


  • Macromolecular Substances
  • Nerve Tissue Proteins
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • tau Proteins