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Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing
Open accessAbstract
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 (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
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“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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Citations
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“Additionally, therapeutics aimed at increasing or rescuing lysosomal activity should also take into account the role of this organelle in the production of amyloidogenic aggregates (Pasternak et al., 2003; Wang et al., 2009; Sannerud et al., 2016).”
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“Tau is another CMA substrate that is also a genetic risk factor for PD ( 21 ), and tau aggregates, often found in tandem with -synuclein ( 22 ), are particularly prominent in PD patients with cognitive decline, a feature associated with GBA-PD.”
Self-citationCell “Self‐Eating” (Autophagy) Mechanism in Alzheimer's Disease
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Lysosomal Dysfunction Promotes Cleavage and Neurotoxicity of Tau In Vivo
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A Caspase Cleaved Form of Tau Is Preferentially Degraded through the Autophagy Pathway
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“Much data have suggested that endo-lysosomal/autophagic dysfunction is responsible for soluble oligomeric forms and insoluble forms of tau aggregation (Figure 2) [170,171].”
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“Also, the residues 139–143 could be involved in the binding to heparin and the residues 336–343 and 347–351 could be involved in chaperone mediated autophagy (Wang et al., 2009).”
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“Various research have recommended that the genesis of tau oligomers and insoluble accumulations may result because of the disturbance of the autophagy‐lysosomal pathway (Hamano et al., 2008; Wang et al., 2009).”
BackgroundNeurodegenerative Disease Tauopathies
Creekmore, B. C., Watanabe, R., & Lee, E. B. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051222-120750 · Cited by 155
The Role of Chaperone-Mediated Autophagy in Huntingtin Degradation
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“Furthermore, mutant Tau protein involved in Alzheimer’s disease (AD) is also targeted to lysosomes via CMA [22].”
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“agy [82]; however, the situation is less well defined for toxic oligomeric forms of Tau where both degradation”
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Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease
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Chaperone‐mediated autophagy in health and disease
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“Using an inducible neuronal tauopathy model, it has been shown that Tau fragmentation initiates in the cytosol, but it is completed at the lysosomal surface [44].”
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Targeting the mTOR Signaling Network for Alzheimer’s Disease Therapy
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“Autophagy–lysosome system has been demonstrated to be responsible for both tau fragmentation into proaggregating forms and the clearance of tau aggregates [93].”
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“There is evidence that dysfunction of the autophagy-lysosome system contributes to the formation of tau oligomers and insoluble aggregates (Hamano et al., 2008; Wang et al., 2009).”
BackgroundInfluentialTherapeutic strategies for tau mediated neurodegeneration
Yoshiyama, Y., Lee, V. M. ‐., & Trojanowski, J. Q. (2012) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-303144 · Cited by 137
Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice
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“hTau fragments can cause or promote tau aggregation, mitochondrial and lysosomal dysfunction, axonal transport deficits, and increases in NMDA receptor levels [61–65].”
Parkinson's disease: convergence on synaptic homeostasis
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“Interestingly, synaptic proteins are significantly enriched for this “KFERQ” recognition motif (Uytterhoeven et al, 2015), and proteins central to PD (a-Synuclein, LRRK2, Tau) also contain this motif (Cuervo et al, 2004; Wang et al, 2009; Orenstein et al, 2013).”
BackgroundHsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease
Salminen, A., Ojala, J. O., Kaarniranta, K., Hiltunen, M., & Soininen, H. S. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.10.006 · Cited by 131
Chaperone-mediated autophagy: machinery, regulation and biological consequences
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“Tau mutants in the cytosol are targeted for CMA and cleaved by lysosomal enzymes [95].”
BackgroundAutophagy deregulation in neurodegenerative diseases – recent advances and future perspectives
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“This is supported by the demonstrated protective effect of autophagy activation and the concomitant clearance of protein aggregates in some diseases such as HD (Ravikumar et al. 2004; Shibata et al. 2006; Sarkar and Rubinsztein 2008; Wang et al. 2009a).”
BackgroundResultInfluentialCrucial role of protein oligomerization in the pathogenesis of Alzheimer's and Parkinson's diseases
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Xu, Y., Du, S., Marsh, J. A., Horie, K., Sato, C., Ballabio, A., Karch, C. M. M., Holtzman, D. M., & Zheng, H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0738-0 · Cited by 124
Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion
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“Consistent with these reports, activation of autophagy reduces MAPT levels in cultured cells and ameliorates MAPT pathology in MAPT-overexpressing mice [60,63], while the perturbation of lysosomal function induced aggregation of MAPT into tangle-like structures [62].”
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“Several studies have shown that hyperphosphorylated tau can be cleared by the autophagy pathway [3, 35, 36] and aggregation of pathological p-tau and SQSTM1/p62 could result from defective autophagy lysosomal clearance [37, 38].”
Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets
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“More recent work has implicated the autophagy-lysosomal system in tau fragmentation and the clearance of tau aggregates (Wang et al. 2009).”
BackgroundThe Role of Tau Oligomers in the Onset of Alzheimer's Disease Neuropathology
Cárdenas-Aguayo, M. D. C., Gómez-Virgilio, L., DeRosa, S., & Meraz-Ríos, M. A. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500148z · Cited by 120
Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics
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“Besides the ubiquitination-proteasome pathway, the autophagy-lysosome pathway is also involved in tau degradation (Wang et al. 2009).”
Propagation of Tau via Extracellular Vesicles
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“Recently, increasing evidence has indicated that disruption of CMA is correlated with the pathogenesis of Parkinson’s disease (Alvarez-Erviti et al., 2010; Cuervo et al., 2004; Yang et al., 2009) and Alzheimer disease (Liu et al., 2009; Wang et al., 2009).”
Autophagy in Human Health and Disease: Novel Therapeutic Opportunities
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“In particular, consistent with previous studies using traditional mutagenesis, the (275)VQIINK(280) and (306)VQIVYK(311) hexapeptide motifs were found to be critical for binding these chaperones to tau (26, 27).”
BackgroundPotential Contribution of Exosomes to the Prion-Like Propagation of Lesions in Alzheimer’s Disease
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“The oligomers of TauRD1K280 can further interfere with lysosomal function and lead to lysosome leakage (Wang et al., 2009).”
BackgroundInfluentialAutophagy in inflammation, infection, neurodegeneration and cancer
Arroyo, D. S., Gaviglio, E. A., Ramos, J. M. P., Bussi, C., Rodriguez‐Galán, M. C., & Iribarren, P. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.11.001 · Cited by 114
“Supporting these data, 3-MA (autophagy inhibitor) increases tau aggregation and toxicity, and rapamycin (autophagy inductor) decreases toxicity in cells that overexpress mutant tau [128,140].”
Tau Protein Squired by Molecular Chaperones During Alzheimer’s Disease
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“demonstrated that tau degradation is through macroautophagy [49].”
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“Autophagy can be induced as a compensatory degradation system when the UPS is impaired (206,207), and hsp70 chaperones tau to lysosomes via chaperonemediated autophagy (208).”
BackgroundTherapeutic strategies for the treatment of tauopathies: Hopes and challenges
Khanna, M. R., Kovalevich, J., Lee, V. M. ‐., Trojanowski, J. Q., & Brunden, K. R. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.006 · Cited by 116
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BackgroundAutophagy–lysosomal-associated neuronal death in neurodegenerative disease
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“Interestingly, Tau is degraded via the autophagic-lysosomal system, whereby Tau aggregates are cleared via macroautophagy [155].”
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“Tau function and localization are regulated by post-translational modifications (PTMs); for example, phosphorylation, acetylation, and proteolysis (Johnson and Stoothoff, 2004; Min et al., 2010; Wang et al., 2009).”
BackgroundChaperone‐mediated autophagy: Molecular mechanisms, biological functions, and diseases
Yao, R., & Shen, J. (2023) · MedComm · doi:10.1002/mco2.347 · Cited by 111
Autophagy: A double-edged sword in Alzheimer’s disease
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“Alzheimer’s disease; amyloid precursor protein; amyloid-β; autophagy; secretases Review”
Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment
Garg, S., Timm, T., Mandelkow, E.-M., Mandelkow, E., & Wang, Y. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.09.008 · Cited by 103
“Electrophoresis and Western blot analysis were done as described previously (Wang et al., 2009).”
BackgroundMethodPossible Mechanisms of Tau Spread and Toxicity in Alzheimer’s Disease
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Metadata
- 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)
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- 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 › 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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