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

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