CHIP targets toxic α-synuclein oligomers for degradation

Julie E. Tetzlaff, Preeti Putcha, Tiago F. Outeiro, Alexander Ivanov, Oksana Berezovska, Bradley T. Hyman, Pamela J. McLean

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113 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)17962-17968
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number26
DOIs
StatePublished - Jun 27 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tetzlaff, J. E., Putcha, P., Outeiro, T. F., Ivanov, A., Berezovska, O., Hyman, B. T., & McLean, P. J. (2008). CHIP targets toxic α-synuclein oligomers for degradation. Journal of Biological Chemistry, 283(26), 17962-17968. https://doi.org/10.1074/jbc.M802283200