The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
Abstract
Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.
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“Induction of Hsp70 by geldanamycin promotes tau degradation both in vitro and in vivo, whereas deletion of CHIP increases the accumulation of phosphorylated tau and caspase-3 cleaved tau [167, 171].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [167]
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Metadata
- Authors
- Petrucelli, L.
- Affiliations
- Mayo Clinic in Florida (US)
- Corresponding author
- Petrucelli, L.
- ORCID
- Petrucelli, L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-01-28
- Volume
- 13
- Issue
- 7
- Pages
- 703-714
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2168079270
- Cited by
- 723
- References
- 41
- Citations by year
- 2026: 29 · 2025: 36 · 2024: 32 · 2023: 32 · 2022: 37 · 2021: 37 · 2020: 36 · 2019: 25 · 2018: 35 · 2017: 31 · 2016: 31 · 2015: 38 · 2014: 34 · 2013: 28 · 2012: 31
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS041816, R01-NS41816-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- CHIP, HSP70, tau protein, ubiquitination, protein degradation, tau aggregation, molecular chaperones, ubiquitin ligase, geldanamycin, heat shock factor 1, tauopathy, Alzheimer's disease, Parkinson's disease, proteasome
- MeSH terms
- Heat Shock Transcription Factors, Animals, Cell Line, Detergents, DNA-Binding Proteins, Genetic Vectors, Humans, Immunohistochemistry, Lac Operon, Models, Genetic, Mutation, Nuclear Proteins, Protein Binding, Quinones, Subcellular Fractions, Transcription Factors, Transfection, Blotting, Western, Benzoquinones, tau Proteins, Molecular Chaperones, HSP70 Heat-Shock Proteins, Transgenes, COS Cells, Ubiquitin, Drosophila Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Lactams, Macrocyclic, Immunoprecipitation, Mice
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