alpha-synuclein fibrillogenesis is nucleation-dependent - Implications forthe pathogenesis of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologic ally characterized by the presence of intracytoplasmic Lewy bodies, the maj or components of which are filaments consisting of alpha-synuclein, Two rec ently identified point mutations in a-synuclein are the only known genetic causes of PD, alpha-Synuclein fibrils similar to the Lewy body filaments ca n be formed in vitro, and we have shown recently that both PD-linked mutati ons accelerate their formation. This study addresses the mechanism of alpha -synuclein aggregation: we show that (i) it is a nucleation-dependent proce ss that can be seeded by aggregated alpha-synuclein functioning as nuclei, (ii) this fibril growth follows first-order kinetics with respect to alpha- synuclein concentration, and (iii) mutant alpha-synuclein can seed the aggr egation of wild type alpha-synuclein, which leads us to predict that the Le wy bodies of familial PD patients with a-synuclein mutations will contain b oth, the mutant and the wild type protein. Finally (iv), we show that wild type and mutant forms of alpha-synuclein do not differ in their critical co ncentrations. These results suggest that differences in aggregation kinetic s of alpha-synucleins cannot be explained by differences in solubility but are due to different nucleation rates, Consequently, alpha-synuclein nuclea tion may be the rate-limiting step for the formation of Lewy body alpha-syn uclein fibrils in Parkinson's disease.