Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologic ally characterized by the presence of intracytoplasmic Lewy bodies, the maj or component of which are filaments consisting of alpha-synuclein. Two rece ntly identified point mutations in alpha-synuclein are the only known genet ic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiological temperature in vitro. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions , the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for th e A53T mutant protein. These data suggest that the formation of alpha-synuc lein aggregates could be a critical step in PD pathogenesis, which is accel erated by the PD-linked mutations.