HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites
Abstract
Neurofibrillary tangles (NFTs) are a characteristic neuropathological feature of Alzheimer's disease (AD), and molecular chaperones appear to be involved in the removal of disease‐associated hyperphosphorylated tau, a primary component of NFTs. Here, novel HSP90 inhibitors were used to examine the impact of chaperone elevation on clearance of different tau species in transfected cells using a unique quantitative assay. The HSP90 inhibitors reduced levels of tau phosphorylated at proline‐directed Ser/Thr sites (pS202/T205, pS396/S404) and conformationally altered (MC‐1) tau species, an epitope that is immeasurable by standard Western blot techniques. The selective clearance of these phospho‐tau species and MC‐1 tau was mediated via the proteasome, while lysosomal‐mediated tau degradation seems to lack specificity for certain tau species, suggesting a more general role in total tau removal. Interestingly, tau phosphorylated at S262/S356 within the tau microtubule binding domain was minimally affected by chaperone induction. Overall, our data show that chaperone induction results in the selective clearance of specific phospho‐tau and conformationally altered tau species mediated by the proteasome; however, the apparent stability of pS262/S356 tau may also explain why MARK is able to regulate normal tau function yet still be linked to the initiation of pathogenic tau hyperphosphorylation in AD.
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Aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system.
“The majority of tau species (including tau lacking phosphorylation at Ser262/356) are degraded by the proteasome [20], while aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system [79–84].”
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Self-citation
- Authors
- Dickey, C. A., Dunmore, J., Lu, B., Wang, J., Lee, W. C., Kamal, A., Burrows, F., Eckman, C., Hutton, M., & Petrucelli, L.
- Affiliations
- Mayo Clinic (US)
- Stanford University (US)
- Mayo Clinic Jacksonville College of Medicine Jacksonville Florida
- Conforma Therapeutics Corporation San Diego California
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2006-02-07
- Volume
- 20
- Issue
- 6
- Pages
- 753-755
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2149746962
- Cited by
- 160
- References
- 3
- Citations by year
- 2025: 1 · 2024: 6 · 2023: 6 · 2022: 2 · 2021: 1 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 8 · 2016: 7 · 2015: 5 · 2014: 12 · 2013: 12 · 2012: 12
- FWCI
- 8.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (PO1 AG17216)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau hyperphosphorylation, Hsp90 inhibitors, heat shock proteins, molecular chaperones, neurofibrillary tangles, Alzheimer's disease, proteasomal degradation, lysosomal degradation, MARK kinases, protein clearance
- MeSH terms
- Animals, Binding Sites, Cells, Cultured, Cricetinae, Heat-Shock Proteins, Humans, Neurons, Phosphorylation, Phosphoserine, Phosphothreonine, Proline, tau Proteins, Mice
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