Current hypotheses concerning the mechanism of neuronal cell death in Parkinson's disease (PD) and related synucleopathies propose a functional interaction between parkin and a-synuclein (alphaS). Recently parkin was shown to suppress mutant alphaS-induced toxicity in primary neurons, providing a basis for an association between these proteins and neuronal loss [Neuron 36 (2000) 10071019]. We have asked if a similar association could be made between wild-type (wt) aS and parkin. We examined inducible overexpression of alphaS in SHSY-5Y cells through adenoviral infection under conditions which produce cellular toxicity through a reduction in ATP levels. We demonstrate that parkin suppresses toxicity induced by mutant (A53T) and wt ccS. Parkin over-expression was also associated with the appearance of higher molecular weight alphaS-immunoreactive bands by Western blot analysis. These data, consistent with a protective role for parkin, extend previous findings to include a functional association between parkin and the wt form of aS. (C) 2003 Elsevier Inc. All rights reserved.