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Cited by 619Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing

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Wang, Yipeng, Martinez-Vicente, Marta, Krüger, Ulrike, Kaushik, Susmita, Wong, Esther, Mandelkow, Eva-Maria, Cuervo, Ana Maria, Mandelkow, Eckhard·2009·Human Molecular Genetics
DOI 10.1093/hmg/ddp367PMC PMC2758146
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Abstract

Aggregation and cleavage are two hallmarks of Tau pathology in Alzheimer disease (AD), and abnormal fragmentation of Tau is thought to contribute to the nucleation of Tau paired helical filaments. Clearance of the abnormally modified protein could occur by the ubiquitin-proteasome and autophagy-lysosomal pathways, the two major routes for protein degradation in cells. There is a debate on which of these pathways contributes to clearance of Tau protein and of the abnormal Tau aggregates formed in AD. Here, we demonstrate in an inducible neuronal cell model of tauopathy that the autophagy-lysosomal system contributes to both Tau fragmentation into pro-aggregating forms and to clearance of Tau aggregates. Inhibition of macroautophagy enhances Tau aggregation and cytotoxicity. The Tau repeat domain can be cleaved near the N terminus by a cytosolic protease to generate the fragment F1. Additional cleavage near the C terminus by the lysosomal protease cathepsin L is required to generate Tau fragments F2 and F3 that are highly amyloidogenic and capable of seeding the aggregation of Tau. We identify in this work that components of a selective form of autophagy, chaperone-mediated autophagy, are involved in the delivery of cytosolic Tau to lysosomes for this limited cleavage. However, F1 does not fully enter the lysosome but remains associated with the lysosomal membrane. Inefficient translocation of the Tau fragments across the lysosomal membrane seems to promote formation of Tau oligomers at the surface of these organelles which may act as precursors of aggregation and interfere with lysosomal functioning.

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  • Disruption of the autophagy-lysosomal pathway is a pathological hallmark in human tauopathy brain.

    “Disruption of the autophagy-lysosomal pathway (ALP) is another pathological hallmark in human tauopathy brain (Bain et al., 2019; Piras et al., 2016; Wang et al., 2009).”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Wang et al., 2009

    The Discussion (page unavailable) states that the autophagy–lysosomal system is disturbed in Alzheimer disease brain, and the Introduction says lysosomal alterations in Alzheimer disease are well established. The paper does not establish that this disruption is a pathological hallmark across human tauopathies; its own tauopathy experiments use a cell model. (LLM, conf=0.84)

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  • Early tau post-translational modifications lead to misfolding, mislocalization, oligomerization, and changes in solubility, and these events appear to be determinant toxicity effectors.

    “Cumulative evidence from murine tauopathy models and postmortem patient brain studies suggests that early tau post-translational modifications lead to misfolding, mislocalization, oligomerization, and changes in solubility. These events appear to be determinant toxicity effectors”

    From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Wang et al., 2009

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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)
  • Albert Einstein College of Medicine (US)
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2009-08-04
Volume
18
Issue
21
Pages
4153-4170
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddp367
PMC
PMC2758146
OpenAlex
W2133548029
Cited by
617
References
72
Citations by year
2026: 25 · 2025: 35 · 2024: 30 · 2023: 28 · 2022: 38 · 2021: 43 · 2020: 45 · 2019: 34 · 2018: 37 · 2017: 32 · 2016: 41 · 2015: 41 · 2014: 28 · 2013: 30 · 2012: 45
FWCI
28.59
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
Funders
  • 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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tau protein, tau aggregation, lysosomal processing, autophagy-lysosome pathway, chaperone-mediated autophagy, cathepsin L, macroautophagy, Alzheimer's disease, tauopathy, lysosomal membrane, tau oligomers, protein clearance
MeSH terms
Animals, Autophagy, Humans, Lysosomes, Microtubule-Associated Proteins, Models, Biological, Mutation, Peptide Fragments, Phagosomes, Protein Binding, Blotting, Western, tau Proteins, Protein Transport, Tauopathies, Cell Line, Tumor, HSC70 Heat-Shock Proteins, Mice, Protein Multimerization, Cathepsin L

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