The oxidation state of DJ-1 regulates its chaperone activity toward α-synuclein

Dj-1 has been reported to have chaperone activity by preventing the aggregation of some proteins, and by structural analogy to Hsp31. The L166P mutation has been linked to a familial early onset form of Parkinson's disease (PD). Since the aggregation of alpha-synuclein is believed to be a critical step in the etiology of PD, we have investigated the interaction of wild-type Dj-1 and its oxidized forms with a-synuclein. Native (unoxidized) Dj-1 did not inhibit a-synuclein fibrillation, and no evidence for stable interactions between alpha-synuclein and native Dj-1 was observed. However, Dj-1 is very susceptible to oxidation by the addition of two oxygen atoms to form the sulfinic acid of Cys106 (20 Dj-1) (no 10 oxidized state is detectable). 20 Dj-1 was readily prepared by the addition of H2O2 at concentrations up to a 20-fold molar excess. The oxidation of Cys106 to the sulfinic acid had minimal effect on the structural properties of Dj-1. However, 20 Dj-1 was very effective in preventing the fibrillation of a-synuclein, and only this form of Dj-1 appears to have significant antiaggregation properties against alpha-synuclein. Further oxidation of Dj-1 leads to loss of some secondary structure, and to loss of the ability to inhibit a-synuclein fibrillation. Our observations confirm the suggestion that Dj-1 may act as an oxidative-stress-induced chaperone to prevent a-synuclein fibrillation. Since oxidative stress has been associated with PD, this observation may explain why mutations of Dj-1 could be a contributing factor in PD, and also indicates that excess oxidative stress could also lead to enhanced a-synuclein aggregation and hence PD. (c) 2005 Elsevier Ltd. All rights reserved.