Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation
Open accessAbstract
Tau aggregation characterizes a series of neurodegenerative diseases including AD and other tauopathies. The distribution of Tau deposits correlates with the loss of neurons in these neurodegenerative diseases, and Tau-induced toxicity depends on its ability to aggregate. We have used an inducible cell model to study the expression of Tau variants, the buildup of aggregates, and their removal by the autophagy-lysosomal system. Incomplete chaperone-mediated autophagy of Tau generates amyloidogenic fragments that promote aggregation. The Tau aggregates are removed from cells by macroautophagy. Thus the two autophagic pathways could become possible therapeutic targets.
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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].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [80]
The paper’s discussion of tau degradation (page unavailable) says aggregated tau is removed by macroautophagy and tau phosphorylated at KXGS motifs in the repeat domains can be degraded by the autophagy-lysosomal system. Our copy does not identify Ser262/356 specifically, so it does not establish that site-specific part of the claim. (LLM, conf=0.82)
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- Authors
- Wang, Y., Martinez-Vicente, M., Krüger, U., Kaushik, S., Wong, E., Mandelkow, E.-M., Cuervo, A. M., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Yeshiva University (US)
- Corresponding author
- Mandelkow, Eckhard
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2010-01
- Volume
- 6
- Issue
- 1
- Pages
- 182-183
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- OpenAlex
- W2013581014
- Cited by
- 90
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2022: 5 · 2021: 9 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 6 · 2014: 7 · 2013: 6 · 2012: 10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- American Liver Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (AG031782, NS038370)
- National Institute on Aging (P01AG031782, AG031782)
- National Institute of Neurological Disorders and Stroke (NS038370, P50NS038370)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- tau aggregation, macroautophagy, chaperone-mediated autophagy, autophagy-lysosome pathway, Alzheimer's disease, tauopathy, neurodegeneration, therapeutic target
- MeSH terms
- Animals, Autophagy, Cells, Humans, Models, Biological, tau Proteins, Molecular Chaperones, Tauopathies, Plaque, Amyloid
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