Degradation of alpha-synuclein by proteasome

Mutations in alpha-synuclein are known to be associated with Parkinson's di sease (PD), The coexistence of this neuronal protein with ubiquitin and pro teasome subunits in Lewy bodies in sporadic disease suggests that alteratio ns of alpha-synuclein catabolism may contribute to the pathogenesis of PD. The degradation pathway of alpha-synuclein has not been identified nor has the kinetics of this process been described. We investigated the degradatio n kinetics of both wild-type and A53T mutant 6XHis-tagged alpha-synuclein i n transiently transfected SH-SY5Y cells. Degradation of both isoforms follo wed first-order kinetics over 24 h as monitored by the pulse-chase method. However, the t(1/2) of mutant alpha-synuclein was 50% longer than that of t he wild-type protein (p < 0.01). The degradation of both recombinant protei ns and endogenous alpha-synuclein in these cells was blocked by the selecti ve proteasome inhibitor beta-lactone (40 mu M), indicating that both wild-t ype and A53T mutant alpha-synuclein are degraded by the ubiquitin-proteasom e pathway. The slower degradation of mutant alpha-synuclein provides a kine tic basis for its intracellular accumulation, thus favoring its aggregation .