The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
The Co-chaperone Carboxyl Terminus of Hsp70-interacting Protein (CHIP) Mediates α-Synuclein Degradation Decisions between Proteasomal and Lysosomal Pathways
Open accessAbstract
Alpha-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 alpha-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 alpha-synuclein aggregation. We demonstrate that CHIP is a component of Lewy bodies in the human brain, where it colocalizes with alpha-synuclein and Hsp70. In a cell culture model, endogenous CHIP colocalizes with alpha-synuclein and Hsp70 in intracellular inclusions, and overexpression of CHIP inhibits alpha-synuclein inclusion formation and reduces alpha-synuclein protein levels. We demonstrate that CHIP can mediate alpha-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 alpha-synuclein toward the lysosomal degradation pathway. Furthermore, alpha-synuclein, synphilin-1, and Hsp70 all coimmunoprecipitate with CHIP, raising the possibility of a direct alpha-synuclein-CHIP interaction. The fact that the tetratricopeptide repeat domain is required for the effects of CHIP on alpha-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.
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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
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Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
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Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease
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CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
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CHIP is a chaperone‐dependent E3 ligase that ubiquitylates unfolded protein
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Cited by
A Gene Network Regulating Lysosomal Biogenesis and Function
Sardiello, M., Palmieri, M., di Ronza, A., Medina, D. L., Valenza, M., Gennarino, V. A., Di Malta, C., Donaudy, F., Embrione, V., Polishchuk, R. S., et al. (2009) · Science · doi:10.1126/science.1174447 · Cited by 2,543
Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies
Ciechanover, A., & Kwon, Y. T. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.117 · Cited by 898
Chaperone-mediated autophagy: a unique way to enter the lysosome world
Kaushik, S., & Cuervo, A. M. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.05.006 · Cited by 850
Ubiquitination and selective autophagy
Shaid, S., Brandts, C. H., Serve, H., & Dikic, I. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2012.72 · Cited by 800
Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3
Gamerdinger, M., Hajieva, P., Kaya, A. M., Wolfrum, U., Hartl, F. U., & Behl, C. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.29 · Cited by 522
Metadata
- Authors
- Shin, Y., Klucken, J., Patterson, C., Hyman, B. T., & McLean, P. J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 280
- Issue
- 25
- Pages
- 23727-23734
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1984136850
- Cited by
- 329
- References
- 9
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Shin, Y., Klucken, J., Patterson, C., Hyman, B. T., & McLean, P. J. (2005). The Co-chaperone Carboxyl Terminus of Hsp70-interacting Protein (CHIP) Mediates α-Synuclein Degradation Decisions between Proteasomal and Lysosomal Pathways. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m503326200
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