α-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome

alpha -Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations in familial cases of the disease and its presence in Lewy bodies. Here we show that overexpression of wild-type human alpha -synuclein is sufficient to induce inclusion formation in SH-SV5Y cells. In this cellular model, proteasome inhibition leads to an increase of a-synuclein accumulation in vivo without ubiquitylation. In accordance, we find that in vitro, unmodified alpha -synuclein can be directly degraded by the 20S proteasome. These findings suggest an ubiquitin-independent mechanism of proteasomal degradation for a-synuclein and other natively unfolded proteins. (C) 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.