TY - JOUR
T1 - The Co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates α-synuclein degradation decisions between proteasomal and lysosomal pathways
AU - Shin, Youngah
AU - Klucken, Jochen
AU - Patterson, Cam
AU - Hyman, Bradley T.
AU - McLean, Pamela J.
PY - 2005/6/24
Y1 - 2005/6/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=21244499845&partnerID=8YFLogxK
U2 - 10.1074/jbc.M503326200
DO - 10.1074/jbc.M503326200
M3 - Article
C2 - 15845543
AN - SCOPUS:21244499845
SN - 0021-9258
VL - 280
SP - 23727
EP - 23734
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -