α-Synuclein aggregation and toxicity play a major role in Parkinson's disease and dementia with Lewy bodies. Hsp70 is a multipurpose stress response chaperone protein that mediates both refolding and degradation of misfolded proteins. We have shown that Hsp70 is able to block both α-synuclein toxicity and aggregation. Here we introduce a mutation into the ATPase domain of Hsp70 (K71S) and demonstrate that this abolishes Hsp70 refolding activity. Nonetheless, Hsp70K71S continues to mediate α-synuclein degradation and blocks aggregate formation. In contrast to wild type Hsp70, the ATPase domain mutant mediates α-synuclein degradation through a non-proteasome inhibitor sensitive pathway. Although Hsp70K71S can diminish levels of α-synuclein to an even greater extent than Hsp70, HSP70K71S does not protect against α-synuclein toxicity. The Hsp70K71S mutant appears to dissociate the formation of aggregates, which it blocks, and toxicity, which it does not block. These data suggest that the ability of Hsp70 to prevent toxicity is distinct from degradation of α-synuclein and is dependent on its ATPase domain.
|Number of pages||7|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 3 Dec 2004|
- Dementia with Lewy bodies
- Parkinson's disease
- Protein aggregation