The Co-chaperone Carboxyl Terminus of Hsp70-interacting Protein (CHIP) Mediates α-Synuclein Degradation Decisions between Proteasomal and Lysosomal Pathways

• Published in: The Journal of biological chemistry Vol. 280; no. 25; pp. 23727 - 23734
• Main Authors: Shin, Youngah, Klucken, Jochen, Patterson, Cam, Hyman, Bradley T., McLean, Pamela J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-06-2005
• Subjects: alpha-Synuclein; Cell Line, Tumor; Humans; Hydrolysis; Lewy Bodies - metabolism; Lysosomes - metabolism; Molecular Chaperones - metabolism; Molecular Chaperones - physiology; Nerve Tissue Proteins - metabolism; Proteasome Endopeptidase Complex - metabolism; Synucleins; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Protein Ligases - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M503326200

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 coimmunoprecipitate 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.