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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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Autophagic Pathways to Clear the Tau Aggregates in Alzheimer’s Disease
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“Normal tau proteins stabilize the structure of microtubules in neurons; however, in disease models misfolded and cleaved tau fragments are unable to perform their regular function and promote the nucleation and accumulation of PHFs on the surface of lysosomes, thereby blocking the lysosome-autophagy pathway [45].”
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Cathepsin D regulates cerebral Aβ42/40 ratios via differential degradation of Aβ42 and Aβ40
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“CMA is an important pathway for the clearance of oxidized cytosolic proteins, and several proteins associated with various neuropathic pathogeneses, such as tau and α‐synuclein, are bonafide CMA substrates.(122,123) Interestingly, inhibition of Hsp90 with GDA, a pan‐Hsp90 inhibitor, was found to significantly activate…”
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Wang, D., Chan, C., Cherry, S., & Hiesinger, P. R. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1201-4 · Cited by 74
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InfluentialInvolvement of molecular chaperone in protein-misfolding brain diseases
Wankhede, N. L., Kale, M. B., Upaganlawar, A. B., Taksande, B. G., Umekar, M. J., Behl, T., Abdellatif, A. A. H., Bhaskaran, P. M., Dachani, S. R., Sehgal, A., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112647 · Cited by 73
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“Although, many neurodegenerative disease-associated pathogenic proteins, such as tau, -synuclein and huntingtin, are degraded by CMA (20-22), whether APP, another important”
BackgroundMechanism and Regulation of Autophagy and Its Role in Neuronal Diseases
Hu, Z., Yang, B., Mo, X., & Xiao, H. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8921-4 · Cited by 69
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Autophagy Modulation for Alzheimer’s Disease Therapy
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Role of the Lipid Membrane and Membrane Proteins in Tau Pathology
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Alzheimer’s disease and the autophagic-lysosomal system
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Chaperone mediated autophagy in aging: Starve to prosper
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Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation
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Tangles, Toxicity, and Tau Secretion in AD – New Approaches to a Vexing Problem
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“Cathepsin L has been shown to generate aggregation-prone fragments mutant but not wild-type tau via association with Lamp2A and Hsc70 on the cytosolic face of the lysosomal membrane (177).”
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“Mutant Tau protein can lower CMA activity by interacting with LAMP2A and prevent translocation to the lysosome lumen [70].”
BackgroundThe Role of Glial Cell Senescence in Alzheimer's Disease
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“…to the accumulation of misfolded proteins within neurons (Cozachenco et al. 2023; Barmaki et al. 2023), while impaired phagocytosis and disruption of lysosomal degradation pathways halt Aβ and tau aggregates' clearance by glial cells (Kreher et al. 2021; Tajbakhsh et al. 2021; Wang et al. 2009).”
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“Moreover, impaired lysosomal membrane integrity was also emerged in AD patients [80], and tau has been reported to perturb lysosomal permeability by binding the membrane of lysosomes both in vitro and in vivo [76, 81].”
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Huang, Y., Wu, Z., & Zhou, B. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2042-8 · Cited by 58
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Curcumin improves tau-induced neuronal dysfunction of nematodes
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“Tau fragments that consist of the microtubule-binding domain are highly prone to aggregation (Fatouros et al., 2012; Wang et al., 2009).”
The Implications of Autophagy in Alzheimer’s Disease
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Hippocampal Endosomal, Lysosomal, and Autophagic Dysregulation in Mild Cognitive Impairment
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Self-citationIntrinsic Tau Acetylation Is Coupled to Auto-Proteolytic Tau Fragmentation
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“In this regard, we note that mass spectrometry analysis of the ~12 kDa tau fragment identified an extreme N-terminal sequence (341)SEKLDFKDR(349) that is immediately adjacent to a putative recognition motif for chaperone-mediated autophagy (CMA), (336)QVEVK(340) [56].”
BackgroundDysfunction of chaperone-mediated autophagy in human diseases
Liao, Z., Wang, B., Liu, W., Xu, Q., Hou, L., Song, J., Guo, Q., & Li, N. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-020-04006-z · Cited by 56
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Key Peptides and Proteins in Alzheimer’s Disease
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“Furthermore, CMA also contributes to the degradation of TauRD1K280 (a truncated tau expressing the pro-aggregated repeat domain with the 1K280 deletion mutation) and the A152T mutant tau (Wang et al., 2009; Caballero et al., 2018), both of which retain the KFERQ motifs.”
BackgroundInfluentialSeki, T., Yoshino, K.-I., Tanaka, S., Dohi, E., Onji, T., Yamamoto, K., Hide, I., Paulson, H. L., Saito, N., & Sakai, N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031232 · Cited by 48
“Although there are several reports concerning CMA in Parkinson’s disease [8,9,10,11] and Alzheimer’s disease [12,13], the role of CMA in various neuronal functions and in other neurodegenerative diseases remains unknown.”
BackgroundBai, B., Zhang, G., Li, Y., Wang, Y., Sujata, S., Zhang, X., Wang, L., Zhao, L., & Wu, Y. (2022) · The Plant Journal · doi:10.1111/tpj.16029 · Cited by 46
Compromised autophagy and mitophagy in brain ageing and Alzheimer’s diseases.
Caponio, D., Veverová, K., Zhang, S.-Q., Shi, L., Wong, G., Vyhnalek, M., & Fang, E. F. (2022) · Aging Brain · doi:10.1016/j.nbas.2022.100056 · Cited by 45
“11 aggregation and interfere with lysosomal functioning [138].”
BackgroundProteasome Inhibition Drives HDAC6-Dependent Recruitment of Tau to Aggresomes
Guthrie, C. R., & Kraemer, B. C. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9502-x · Cited by 49
“Furthermore, both the UPS and lysosomal systems have been demonstrated to be disrupted in AD and may also be dysfunctional in other disorders exhibiting tau pathology (Wang et al. 2009; Boland et al. 2008; Nixon 2007).”
BackgroundPolydoro, M., de Calignon, A., Suárez‐Calvet, M., Sanchez, L., Kay, K. R., Nicholls, S. B., Roe, A. D., Pitstick, R., Carlson, G. A., Gómez‐Isla, T., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0881-13.2013 · Cited by 47
“Possibly, human tau soluble oligomeric species may impair the proteasome- or macroautophagy-mediated protein turn-over and degradation that have been implicated in tau clearance (Berger et al., 2007; Dickey et al., 2007; Carrettiero et al., 2009; Wang et al., 2009; Tai et al., 2012).”
BackgroundThe autophagy-lysosomal pathway
Kenney‐Jung, D. L., & Benarroch, E. E. (2015) · Neurology · doi:10.1212/wnl.0000000000001860 · Cited by 46
“Chaperonemediated autophagy delivers cytosolic tau to lysosomes for limited cleavage; inefficient translocation of the tau fragments across the lysosomal membrane may promote formation of tau oligomers at the surface of these organelles, predisposing to tau aggregation and interfering with lysosomal function.(56) Tau…”
BackgroundInfluentialTiernan, C. T., Combs, B., Cox, K. K., Morfini, G. A., Brady, S. T., Counts, S., & Kanaan, N. M. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.06.030 · Cited by 46
The disorderly conduct of Hsc70 and its interaction with the Alzheimer's-related Tau protein
Taylor, I. R., Ahmad, A., Wu, T., Nordhues, B. A., Bhullar, A., Gestwicki, J. E., & Zuiderweg, E. R. P. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002234 · Cited by 46
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Progressive Supranuclear Palsy and Corticobasal Degeneration
Dickson, D. W., Hauw, J. J., Agid, Y., & Litvan, I. (2011) · Wiley eBooks · doi:10.1002/9781444341256.ch15 · Cited by 48
Impact of Chaperone-Mediated Autophagy in Brain Aging: Neurodegenerative Diseases and Glioblastoma
Auzmendi-Iriarte, J., & Matheu, A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.630743 · Cited by 47
Generation of Tau Aggregates and Clearance by Autophagy in an Inducible Cell Model of Tauopathy
Wang, Y., Krüger, U., Mandelkow, E., & Mandelkow�, E. (2010) · Neurodegenerative Diseases · doi:10.1159/000285516 · Cited by 43
Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities
Wang, L., Banesh, S., Kumar, R., Schedin‐Weiss, S., Tjernberg, L. O., & Winblad, B. G. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70048 · Cited by 47
Connecting chaperone-mediated autophagy dysfunction to cellular senescence
Moreno-Blas, D., Gorostieta-Salas, E., & Castro‐Obregón, S. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.11.001 · Cited by 42
“X histone (γH2AX) (Kang et al., 2015a,b; Wang et al., 2009b).”
Kanno, H., Handa, K., Murakami, T., Aizawa, T., & Ozawa, H. (2022) · Cells · doi:10.3390/cells11071205 · Cited by 47
“The CMA degradation of these protein substrates was shown to be impaired in patients with AD [45,61,79].”
BackgroundModeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease
Jaworski, T., Kügler, S., & LEUVEN, F. V. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/573138 · Cited by 45
“The actual contribution of the mutation to the mechanism underlying the pathogenesis requires a rational explanation in human FTD patients, as well as in the AAV-models.”
Hassiotis, S., Manavis, J., Blumbergs, P. C., Hattersley, K. J., Carosi, J. M., Kamei, M., & Sargeant, T. J. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.13913 · Cited by 44
“Furthermore, two lysosomal proteases, cathepsin L and legumain, are also capable of directly cleaving tau to produce highly aggregate-prone tau truncation products (Wang et al., 2009; Zhang et al., 2014).”
BackgroundChaperone-mediated autophagy: roles in neurodegeneration
Wang, G., & Mao, Z. (2014) · Translational Neurodegeneration · doi:10.1186/2047-9158-3-20 · Cited by 42
Sydow, A., Hochgräfe, K., Könen, S., Cadinu, D., Matenia, D., Petrova, O. M., Joseph, M., Dennissen, F. J. A., & Mandelkow, E. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0281-z · Cited by 42
“Tau) are preferentially degraded by chaperone-mediated autophagy [110].”
Schneider, J. L., Miller, A. M., & Woesner, M. E. (2017) · Einstein Journal of Biology and Medicine · doi:10.23861/ejbm201631752 · Cited by 42
The Role of Beclin-1 Acetylation on Autophagic Flux in Alzheimer’s Disease
Esteves, A. R., Filipe, F., Magalhães, J. D., Silva, D. F., & Cardoso, S. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1483-8 · Cited by 42
Picalm reduction exacerbates tau pathology in a murine tauopathy model
Ando, K., Decker, R. D., Vergara, C., Yilmaz, Z., Mansour, S., Suain, V., Sleegers, K., de Fisenne, M.-A., Houben, S., Potier, M., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02125-x · Cited by 46
Stress and the Etiopathogenesis of Alzheimer’s Disease and Depression
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Inhibition of class I PI3K enhances chaperone-mediated autophagy
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“CMA also regulates the abundance of Tau (MAPT), Huntingtin (HTT), amyloid precursor protein (APP), LRRK2, TDP-43 (TARDBP), and other neurodegeneration-associated peptides (Wang et al., 2009; Huang et al., 2014; Qi et al., 2012; Orenstein et al., 2013; Park et al., 2016; Kaushik and Cuervo, 2018).”
BackgroundLysosomal Fusion Dysfunction as a Unifying Hypothesis for Alzheimer's Disease Pathology
Funk, K. E., & Kuret, J. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/752894 · Cited by 41
“Second, tau contains two sequence motifs for chaperonemediated autophagy [99], a pathway that relies on hsc70 to target substrates directly to the lysosome.”
BackgroundInfluentialCongdon, E. E., Jiang, Y., & Sigurdsson, E. M. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.12.002 · Cited by 38
Brain Injury in the Context of Tauopathies
Abisambra, J. F., & Scheff, S. W. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131019 · Cited by 38
“Cleavage enzymes also process tau yielding truncated fragments, and these activities may be enhanced in disease [49, 59–64].”
BackgroundOpattová, A., Filipčík, P., Cente, M., & Novák, M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121072 · Cited by 41
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Chen, J., Long, Z., Li, Y., Luo, M., Luo, S., & He, G. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4198 · Cited by 42
HDAC6 ZnF UBP as the Modifier of Tau Structure and Function
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Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders
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“Although the underlying mechanisms for this are not yet clear, tau is degraded in the autophagy-lysosome system [41–43], and cholesterol storage in lysosomes of Niemann-Pick type C diseased brain induces lysosomal dysfunction and tau-pathology [44–46].”
Geier, E. G., Bourdenx, M., Storm, N. J., Cochran, J. N., Sirkis, D. W., Hwang, J.-H., Bonham, L. W., Ramos, E. M., Diaz, A., Van Berlo, V., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-1925-9 · Cited by 39
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Endosomal-lysosomal dysfunction in metabolic diseases and Alzheimer's disease
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Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake
La‐Rocque, S. D., Moretto, E., Butnaru, I., & Schiavo, G. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15144 · Cited by 46
“…of tau aggregates (Ahmed et al., 2014; Clavaguera et al., 2009), transgenic mice expressing tau only in the entorhinal cortex (de Calignon et al., 2012; Liu et al., 2012) and using viruses to restrict tau expression in specific brain regions (Dujardin, Lécolle, et al., 2014; Wegmann et al., 2019).”
Background
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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