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Degradation of tau protein by autophagy and proteasomal pathways
Abstract
Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. The impairment of protein-degradation systems might play a role in such processes, as these pathways normally keep tau levels at a low level which may prevent aggregation. Some proteases can process tau and thus contribute to tau aggregation by generating amyloidogenic fragments, but the complete clearance of tau mainly relies on the UPS (ubiquitin–proteasome system) and the ALS (autophagy–lysosome system). In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies.
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“As tau is a target of autophagy80, any deficiencies in processing could lead to increased levels of intracellular tau, including misfolded, damaged or aggregated protein.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [80]
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Ikeda, K., Akiyama, H., Arai, T., Kondo, H., Haga, C., Tsuchiya, K., Yamada, S., Murayama, S., & Hori, A. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01009-0 · Cited by 28
Shemesh, O. A., & Spira, M. E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0689-7 · Cited by 24
Aminopeptidases do not directly degrade tau protein
Chow, K. M., Guan, H., & Hersh, L. B. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-48 · Cited by 24
Pacheco, C. D., Elrick, M. J., & Lieberman, A. P. (2009) · Autophagy · doi:10.4161/auto.5.4.8364 · Cited by 20
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Tau in physiology and pathology
Wang, Y., & Mandelkow, E. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.1 · Cited by 2,251
Self-citationTau-targeting therapies for Alzheimer disease
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Roles of tau protein in health and disease
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Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits
Min, S.-W., Chen, X., Tracy, T. E., Li, Y., Zhou, Y., Wang, C., Shirakawa, K., Minami, S. S., Defensor, E., Mok, S. A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3951 · Cited by 516
Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes
Pajares, M., Jiménez-Moreno, N., García-Yagüe, Á. J., Escoll, M., de Ceballos, M. L., Van Leuven, F., Rábano, A., Yamamoto, M., Rojo, A. I., & Cuadrado, A. (2016) · Autophagy · doi:10.1080/15548627.2016.1208889 · Cited by 392
Metadata
- Authors
- Wang, Y., & Mandelkow, E.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Corresponding author
- Wang, Yipeng
- ORCID
- Wang, Yipeng
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2012-07-20
- Volume
- 40
- Issue
- 4
- Pages
- 644-652
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W2149107089
- Semantic Scholar
- d284a357b1c845f43f0ed4c30e07818cb0344a3c
- Cited by
- 166
- References
- 102
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 18 · 2021: 16 · 2020: 25 · 2019: 11 · 2018: 13 · 2017: 12 · 2016: 16 · 2015: 14 · 2014: 7 · 2013: 6 · 2012: 2
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust
- Bundesministerium für Bildung und Forschung
- Tau Consortium
- Medical Research Council (MC_G1000734)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- tau protein, tau aggregation, protein degradation, ubiquitin-proteasome system, autophagy-lysosome system, Alzheimer's disease, tauopathy, neurodegeneration, proteolytic enzymes, therapeutic target
- MeSH terms
- Animals, Autophagy, Humans, Signal Transduction, tau Proteins, Proteasome Endopeptidase Complex
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