CHIP targets toxic α-synuclein oligomers for degradation

alpha-Synuclein (alpha Syn) can self-associate, forming oligomers, fibrils, and Lewy bodies, the pathological hallmark of Parkinson disease. Current dogma suggests that oligomeric alpha Syn intermediates may represent the most toxic alpha Syn species. Here, we studied the effect of a potent molecular chaperone, CHIP ( carboxyl terminus of Hsp70- interacting protein), on alpha Syn oligomerization using a novel bimolecular fluorescence complementation assay. CHIP is a multidomain chaperone, utilizing both a tetratricopeptide/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 alpha Syn oligomerization and toxicity in a tetratricopeptide domain-dependent, U-box-independent manner by specifically degrading toxic alpha Syn oligomers. We conclude that CHIP preferentially recognizes and mediates degradation of toxic, oligomeric forms of alpha Syn. Further elucidation of the mechanisms of CHIP-induced degradation of oligomeric alpha Syn may contribute to the successful development of drug therapies that target oligomeric alpha Syn by mimicking or enhancing the powerful effects of CHIP.