Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation.
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.
Kotzbauer
Paul T
PT
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. kotzbaue@mail.med.upenn.edu
Giasson
Benoit I
BI
Kravitz
Alexxai V
AV
Golbe
Lawrence I
LI
Mark
Margery H
MH
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D019943:Amino Acid Substitution / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001923:Brain Chemistry; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012995:Solubility; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins