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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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Tau Seeds in Extracellular Vesicles Induce Tau Accumulation in Degradative Organelles of Cells
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“Nevertheless, we localize Tau-pS422 in the ALP which could suggest that the inhibition of caspaseinduced tau cleavage by S422 phosphorylation might be removed locally in the endo-lysosomal environment allowing cathepsin cleavage of tau [56] in order to facilitate the autophagic degradation of its fragments.”
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“…tau protein binds to LAMP2A as a substrate protein of CMA, but LAMP2A cannot completely transport the tau protein into lysosomes, which results in the deposition of the tau protein on lysosomal membranes and thereby leads to lysosome breakage and leakage (Wang et al., 2009; Kanno et al., 2022).”
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Autophagy in Neurodegenerative Diseases
Moussa, C. (2019) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-030-05067-2_10
The Analysis of Exosomal Tau Release and its Regulation
Bradshaw, A. (2018) · UCL Discovery (University College London)
Regulation of Chaperone-Mediated Autophagy by PI3K Signaling
Ziemba, Z. (2020) · Deep Blue (University of Michigan)
Wong, E. S. P. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811353-0.00078-6
Chaperone-mediated autophagy: machinery, regulation and biological consequences
Mao, Y., & Ag, S. B. (2011)
Chaperone-mediated autophagy—mechanisms and disease role
Albornoz, A., Sequeida, Á., Rodríguez, C., & Budini, M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822003-0.00004-8
Im, E., Jiang, Y., Stavrides, P. H., Darji, S., Erdjument‐Bromage, H., Thomas, N. A., Bordi, M., Choi, J. Y., Lee, J., & Nixon, R. A. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4106838
“In AD, disrupted lysosome function contributes to neuritic dystrophy, reduced clearance of β-amyloid and tau, synaptic plasticity deficits, and neurodegeneration (Cataldo et al., 2004; Checler et al., 2021; Nixon, 2007; Wang et al., 2009).”
BackgroundUddin, M. N., Shimonaka, S., & Motoi, Y. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-89906-2.00014-9
Autophagy Regulates Tau Protein Metabolism in Alzheimer’s Disease
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Presenilin-dependent regulation of tau pathology via the autophagy/proteasome pathwayPreprint
del Ser‐Badia, A., Soto-Faguás, C. M., Vecino, R., Rodrı́guez-Álvarez, J., Vicario‐Abejón, C., & Saura, C. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.21.572822
“Considering that pathological tau is eliminated via autophagy (Wang et al., 2009; Kruger et al., 2012; Silva et al., 2020), and PS regulates the autophagic-lysosomal system (see above, (Lee et al., 2010; Neely et al., 2011; Lee et al., 2015)), it is plausible that PS-dependent tau homeostasis could…”
BackgroundMolecular and Cellular Mechanisms of Primary Tauopathies
Gong, S., & Gan, L. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780197640654.003.0056
High reelin expression can explain why the entorhinal cortex is a cradle for Alzheimer’s diseasePreprint
Kobro‐Flatmoen, A., Hussan, J. R., Hunter, P. J., & Omholt, S. W. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.04.655278
Expression of progerin enhances disease-related endpoints in a tau seeding reporter cell system
Han, Z. Z., Kang, S., Gomez‐Cardona, E., Wohlgemuth, S. L., Shmeit, K., Arce, L., Safar, J., Julien, O., & Westaway, D. A. (2025) · GeroScience · doi:10.1007/s11357-025-01737-z
“…VDAC1, LRSAM1, and increased protein level of ATM, EEF1A2, CTTN, UCHL1, RB1CC1, CISD1, RPTOR, WNK1), an important pathway for abnormal tau clearance [44]; and positive regulation of proteasomal ubiquitin-dependent protein catabolic process (increased protein level of SUMO2, AURKA, and FBXO22).”
Impaired MAPT/tau-secretory lysosomes are linked to cognitive vulnerability in Alzheimer patients
Sharma, P., Pallavi, A., Chatterjee, A., Prasad, V. M., Gandasi, N. R., & Saroja, S. R. (2025) · Autophagy · doi:10.1080/15548627.2025.2552905
“The lysosomes are shown to degrade MAPT/tau proteins in vitro [54,55].”
Bichalska-Lach, M., Waniczek, D., Kowalczyk, P., Śnietura, M., Kryj, M., Bednarczyk, M., & Muc‐Wierzgoń, M. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb48010031
“Therefore, abnormalities in this process have been linked to autoimmune diseases and cancer [68].”
Featherby, S. J., Faulkner, E. C., Gordon, A. D., & Ettelaie, C. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01658-7
“…; Fourest-Lieuvin et al. 2023 ; Kopke et al. 1993 ; Meredith et al. 2013; Neddens et al. 2018 ; Rawat et al. 2022 ; Santpere et al. 2006; Sattarov et al. 2024; Stefanoska et al. 2022 ; Takeda et al. 2015 ; Tenreiro et al. 2014; Wagshal et al. 2015 ; Wang et al. 2007, 2009 ; Wegmann et al. 2021 ).”
Jia, N., Guan, H., Zuo, Y., Jeong, Y. Y., Amireddy, N., Rajapaksha, G., Gonzalez, C. U., Jaber, N., Lee, Y.-K., Nissenbaum, M., et al. (2026) · bioRxiv · doi:10.64898/2026.03.23.713823
“It has been established that pathological tau, a defining feature of AD and related tauopathies, is degraded within lysosomes after sequestration within autophagosomes/autophagic vacuoles (AVs) (14-17).”
Rôle des ADAM dans le processus physiopathologique de la maladie d'Alzheimer
Laumet, G. O. (2010) · theses.fr (ABES) · doi:10.70675/94126786zf990z488ezb471z5f1d5686766c
“L’implication d’ADAM10 dans ce mécanisme et dans le métabolisme de l’APP, influançant lui-même la plasticité synaptique (Mucke et al., 2000 ; Puzzo et al., 2008 ; Walsh et al., 2002 ; Wang et al., 2009 ; Yang et al., 2005), est un argument confortant le rôle des métalloprotéases dans la physiopathologie de la MA.”
BackgroundCoulon, P.-G. A. (2014) · theses.fr (ABES) · doi:10.70675/35505ce2z6226z4be3z9fc3za30de5ecacdc
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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