The Co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates α-synuclein degradation decisions between proteasomal and lysosomal pathways

Youngah Shin, Jochen Klucken, Cam Patterson, Bradley T. Hyman, Pamela J. McLean

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Abstract

α-Synuclein is a major component of Lewy bodies, the pathological hallmark of Parkinson disease, dementia with Lewy bodies, and related disorders. Misfolding and aggregation of α-synuclein is thought to be a critical cofactor in the pathogenesis of certain neurodegenerative diseases. In the current study, we investigate the role of the carboxyl terminus of Hsp70-interacting protein (CHIP) in α-synuclein aggregation. We demonstrate that CHIP is a component of Lewy bodies in the human brain, where it colocalizes with α-synuclein and Hsp70. In a cell culture model, endogenous CHIP colocalizes with α-synuclein and Hsp70 in intracellular inclusions, and overexpression of CHIP inhibits α-synuclein inclusion formation and reduces α-synuclein protein levels. We demonstrate that CHIP can mediate α-synuclein degradation by two discrete mechanisms that can be dissected using deletion mutants; the tetratricopeptide repeat domain is critical for proteasomal degradation, whereas the U-box domain is sufficient to direct α-synuclein toward the lysosomal degradation pathway. Furthermore, α-synuclein, synphilin-1, and Hsp70 all co-immunoprecipitate with CHIP, raising the possibility of a direct α-synuclein-CHIP interaction. The fact that the tetratricopeptide repeat domain is required for the effects of CHIP on α-synuclein inclusion morphology, number of inclusions, and proteasomal degradation as well as the direct interaction of CHIP with Hsp70 implicates a cooperation of CHIP and Hsp70 in these processes. Taken together, these data suggest that CHIP acts a molecular switch between proteasomal and lysosomal degradation pathways.

Original languageEnglish (US)
Pages (from-to)23727-23734
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number25
DOIs
StatePublished - Jun 24 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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