CHIP targets toxic alpha -synuclein oligomers for degradation

Chip targets toxic alpha -synuclein oligomers for degradation.

Dept. of Neurology, Alzheimer Disease Research Unit, Massachusetts General Hosptial, Charlestown, MA 02129.

a-Synuclein (aSyn) can self-associate, forming oligomers, fibrils and Lewy bodies, the pathological hallmark of Parkinson's disease (PD). Current dogma suggests that oligomeric aSyn intermediates may represent the most toxic aSyn species. Here, we studied the effect of a potent molecular chaperone, CHIP (Carboxyl terminus of Hsp70-interacting protein), on aSyn oligomerization using a novel bimolecular fluorescence complementation assay (BiFC). CHIP is a multidomain chaperone, utilizing both a TPR/Hsp70 binding domain and a U-box/ubiquitin ligase domain to differentially impact the fate of misfolded proteins. In the current study, we found that co-expression of CHIP selectively reduced aSyn oligomerization and toxicity in a TPR domain dependent, U-box independent manner by specifically degrading toxic aSyn oligomers. We conclude that CHIP preferentially recognizes and mediates degradation of toxic, oligomeric forms of aSyn. Further elucidation of the mechanisms of CHIP-induced degradation of oligomeric aSyn may contribute to the successful development of drug therapies that target oligomeric aSyn by mimicking or enhancing the powerful effects of CHIP.

PMID: 18436529 [PubMed - as supplied by publisher]