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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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“It has been reported that tau can be degraded by lysosomal proteases [55] and, more recently, it was shown that tau fragmentation and clearance can occur by lysosomal processing [56].”
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Young, Z. T., Mok, S., & Gestwicki, J. E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024612 · Cited by 31
“Chaperone-mediated autophagy and the UPS are the major clearance pathways for removing tau (Wong et al. 2008; Wang et al. 2009; Ozcelik et al. 2013).”
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Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer’s Disease
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“Although recent studies using cell models showed that fulllength wild-type Tau was preferentially degraded by macroautophagy (Hamano et al. 2008; Wang et al. 2009), the role of constitutive macroautophagy in recycling of soluble Tau in vivo remains controversial, and the state of phosphorylation…”
BackgroundRole of chaperone-mediated autophagy in degrading Huntington's disease-associated huntingtin protein
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“Once the Tau at the membrane is mutated, it results in CMA blockage with the decrease of the clearance of the mutated proteins [52].”
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Tan, S., & Wong, E. S. P. (2016) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2016.09.084 · Cited by 29
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“Of relevance, the degradation of tau can produce different fragments that bind to Hsc70 being targeted to LAMP-2A by the CMA [131,132].”
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“Although autophagic flux was not directly investigated, the observed reduction of tau protein, a known substrate of autophagy [93], could suggest that the effect is elicited by an increase in autophagic flux, thereby depicting rapamycin as potential candidate for the treatment of MAPT-linked FTD.”
BackgroundSelective autophagy: The new player in the fight against neurodegenerative diseases?
Wu, M.-Y., Song, J., Wang, S.-F., Cai, C.-Z., Li, M., & Lu, J. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.11.009 · Cited by 27
“related proteins have been associated with CMA: neurofibrillary tangles increase when CMA is blocked (Wang et al., 2009); normal tau can be degraded by CMA via targeting motifs at its C-terminus; mutant tau can bind to LAMP-2A and disrupt its lysosomal membrane translocation (Wang et al.”
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ResultSynaptic proteostasis in Parkinson's disease
Nachman, E., & Verstreken, P. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.09.001 · Cited by 27
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“HSP70 transports APP to lysosomes for CMA or endosomal microautophagy (eMI) for degradation to reduce Aβ oligomers levels [215].”
BackgroundLatrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability
Weisová, P., Alvarez, S. P., Kilbride, S. M., Anilkumar, U., Baumann, B., Jordán, J., Bernaś, T., Huber, H. J., Düßmann, H., & Prehn, J. H. M. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.92 · Cited by 26
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“…do not completely translocate into the lysosomal lumen for degradation, despite the existence of two cMa targeting motifs in Tau c-terminal region (179). acetylation of soluble Tau represents an early event in neurodegeneration, and blockade of cMa exacerbates the proliferation of pathogenic Tau…”
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“…and function of these organelles including Aβ generation and tau phosphorylation (Kenessey et al. 1997; Oyama et al. 1998; Hamano et al. 2008; Wang et al. 2009; Hui et al. 2012; Chen et al. 2013; Chesser et al. 2013), and because our recent finding that caffeine blocks LDL endocytosis and…”
Tau Phosphorylation and Aggregation as a Therapeutic Target in Tauopathies
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“However, a recent study in an inducible neuroblastoma cell model of tauopathy has shown that autophagy can both promote tau clearance and tau truncation, resulting in proaggregating fragments [199].”
BackgroundJia, N., Ganesan, D., Guan, H., Jeong, Y. Y., Han, S., Rajapaksha, G., Nissenbaum, M., Kusnecov, A. W., & Cai, Q. (2024) · Autophagy · doi:10.1080/15548627.2024.2392408 · Cited by 27
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“Hyperphosphorylation introduces negative charges on the tau protein, altering electrostatic interactions between amino acid residues and causing conformational changes that may promote tau aggregation [80].”
BackgroundMultivalent protein–protein interactions are pivotal regulators of eukaryotic Hsp70 complexes
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“Also CMA, specifically, has been implicated in the degradation of proteins associated with a number of neurodegenerative diseases as exemplified in tauophaties [42], Parkinson’s disease [43–46] and Huntington’s disease [47, 48].”
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“Impaired chaperone-mediated autophagy (CMA) has been implicated in the accumulation of aggregated tau in AD (Wang et al. 2009), and α-synuclein in Parkinson’s disease (PD) (Cuervo et al.”
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C-reactive protein: the nexus between inflammation and protein misfolding diseases
Roy, A., Zeller, J., Nero, T. L., Klepetko, J., Eisenhardt, S. U., Parker, M. W., McFadyen, J. D., & Peter, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1612703 · Cited by 23
Legal but lethal: functional protein aggregation at the verge of toxicity
Falsone, A., & Falsone, S. F. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00045 · Cited by 22
“An effect in the opposite direction is observed for disease-linked tau fragments, as the failure to process them via CMA leads to the activation of MA (Wang et al., 2009).”
Backgroundβ-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice
Piedrahita, D., Castro-Álvarez, J. F., Boudreau, R. L., Villegas‐Lanau, A., Kosik, K. S., Gallego-Gómez, J. C., & Cardona‐Gómez, G. P. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00498 · Cited by 25
“In addition to the proteasome pathway, macroautophagy is another important mechanism that is involved in the unfolded protein response and is specifically related to aggregated tau (Ikeda et al., 1998; Murakami et al., 1998; Wang et al., 2006a, 2009; Hamano et al., 2008).”
BackgroundRuan, Z., & Ikezu, T. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_11 · Cited by 23
Kelliny, S., Zhou, X., & Bobrovskaya, L. (2025) · Journal of Neuroscience Research · doi:10.1002/jnr.70046 · Cited by 27
“Tau oligomers may interfere with the autophagy-lysosomal pathway (ALP), which plays a role in the clearance of misfolded proteins (Wang et al. 2009; Lim et al. 2001) and degradation of impaired mitochondria.”
Rai, S. K., Khanna, R., Sarbahi, A., Joshi, A., & Mukhopadhyay, S. (2025) · Science Advances · doi:10.1126/sciadv.ads1241 · Cited by 24
“More-over, lysosomal degradation pathways, including autophagy, can serve as a complementary mechanism for removing tau assemblies ( 94 ).”
Altered Proteostasis in Neurodegenerative Tauopathies
Papanikolopoulou, K., & Skoulakis, E. M. C. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-38266-7_7 · Cited by 23
Chopra, G., Shabir, S., Yousuf, S., Kauts, S., Bhat, S. A., Mir, A. H., & Singh, M. P. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03042-8 · Cited by 24
“Tau protein, a microtubule-associated protein, represents another misfolded protein found commonly in NDs such as AD, PD, HD, and frontotemporal dementia with parkinsonism (FTDP) [15, 39, 54].”
BackgroundFessel, W. J. (2017) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317517698790 · Cited by 21
Time course of Tau toxicity and pharmacologic prevention in a cell model of Tauopathy
Pickhardt, M., Biernat, J., Hübschmann, S., Dennissen, F. J. A., Timm, T., Aho, A., Mandelkow, E., & Mandelkow�, E. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.04.022 · Cited by 21
Research Advances in Chaperone-Mediated Autophagy (CMA) and CMA-Based Protein Degraders
Pan, Z., Huang, X., Liu, M., Jiang, X. L., & He, G. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02681 · Cited by 21
Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction
Krogsaeter, E., McKetney, J., Valiente‐Banuet, L., Marquez, A., Willis, A., Cakir, Z., Stevenson, E. J., Jang, G. Μ., Rao, A. T., Li, E., et al. (2025) · Autophagy · doi:10.1080/15548627.2025.2576613 · Cited by 22
Suppressing Tau Aggregation and Toxicity by an Anti-Aggregant Tau Fragment
Pir, G. J., Choudhary, B. C., Kaniyappan, S., Chandupatla, R., Mandelkow�, E., Mandelkow, E., & Wang, Y. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1326-z · Cited by 20
A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases
Cristofani, R., Crippa, V., Cicardi, M. E., Tedesco, B., Ferrari, V., Chierichetti, M., Casarotto, E., Piccolella, M., Messi, E., Galbiati, M., et al. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00191 · Cited by 24
The fine-tuning of proteolytic pathways in Alzheimer’s disease
Cecarini, V., Bonfili, L., Cuccioloni, M., Mozzicafreddo, M., Angeletti, M., Keller, J. N., & Eleuteri, A. M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2238-6 · Cited by 21
“This process alters the lysosomal membrane integrity and blocks the normal lysosomal functionality finally contributing to AD pathogenesis [139].”
BackgroundLRRK2, alpha-synuclein, and tau: partners in crime or unfortunate bystanders?
Outeiro, T. F., Harvey, K., Dominguez‐Meijide, A., & Gerhardt, E. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180466 · Cited by 20
Seranova, E., Palhegyi, A. M., Verma, S., Dimova, S., Lasry, R., Naama, M., Sun, C., Barrett, T. G., Rosenstock, T. R., Kumar, D., et al. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.024 · Cited by 20
“On the other hand, mutant tau could undergo autophagic degradation [300,301].”
Chaperone-Mediated Autophagy after Spinal Cord Injury
Handa, K., Kanno, H., Matsuda, M., Sugaya, T., Murakami, T., Prudnikova, M., Ozawa, H., & Itoi, E. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2019.6820 · Cited by 22
“…disease and Huntington’s disease, a decrease in CMA activity causes the accumulation of pathogenic proteins such as amyloid-b and Htt. 15,21 On the other hand, other studies have showed that CMA activity is upregulated in damaged neural tissue after traumatic brain injury and cerebral…”
A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease
Li, W., Kui, L., Tsirukis, D. I., Gong, X., & Tang, M. (2020) · Aging and Disease · doi:10.14336/ad.2020.0105 · Cited by 21
“The in vitro experiments and the mouse model showed that Tau binds lysosomal membranes to change its permeability [49, 50].”
BackgroundAutophagy status as a gateway for stress-induced catecholamine interplay in neurodegeneration
Fornai, F., & Puglisi‐Allegra, S. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.01.015 · Cited by 20
Tau Is Truncated in Five Regions of the Normal Adult Human Brain
Friedrich, M. G., Skora, A. S., Hancock, S. E., Mitchell, T. W., Else, P. L., & Truscott, R. J. W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073521 · Cited by 21
Kim, S.-I., Lee, W. K., Kang, S.-S., Lee, S.-Y., Jeong, M.-J., Lee, H. J., Kim, S. S., Johnson, G. V. W., & Chun, W. (2011) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2011.15.2.107 · Cited by 20
“To determine the role of autophagy in tau degradation, tau levels were measured in the presence of 3-MA, autophagic inhibitor [18] or trehalose, autophagic inducer [19].”
BackgroundLiu, X., Huang, S., Wang, X., Tang, B., Li, W., & Mao, Z. (2015) · Neuroscience Bulletin · doi:10.1007/s12264-015-1542-8 · Cited by 21
Zhang, S., Wang, H., Wang, J., Jin, W., Yan, X., Chen, X., Wang, D., Zhao, D., Wang, Y., Cong, D., et al. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174887 · Cited by 19
Inekci, D., Jonesco, D. S., Kennard, S., Karsdal, M. A., & Henriksen, K. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00090 · Cited by 19
“Incomplete CMA of tau is suggested to promote tau aggregation (182) which is a hallmark of several tauopathies including AD (103).”
BackgroundThe unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease
Torres, M., Marcilla-Etxenike, A., Fiol-deRoque, M. A., Escribá, P. V., & Busquets, X. (2015) · APOPTOSIS · doi:10.1007/s10495-015-1099-z · Cited by 19
“Furthermore, the inhibition of autophagy has been correlated with increased hyperphosphorylated tau protein [77].”
NPAS4 Facilitates the Autophagic Clearance of Endogenous Tau in Rat Cortical Neurons
Fan, W., Long, Y., Lai, Y., Wang, X., Chen, G., & Zhu, B. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0692-5 · Cited by 18
Fu, H., Cui, Y., Li, Q., Wang, D., Li, H., Yang, L., Wang, D., & Zhou, J. (2022) · Brain Pathology · doi:10.1111/bpa.13114 · Cited by 18
“The most well-defined role for LAMP-2A is as a receptor for CMA, mediating the lysosomal uptake of selective substrates related to neurodegenerative diseases, including α-synuclein and leucine-rich repeat kinase-2 in Parkinson’s disease [24–26], tau protein in Alzheimer’s disease [27], and huntingtin in Huntington’s d…”
BackgroundChaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy
Liu, Y., Tan, M., & Tan, M. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-022-04640-9 · Cited by 22
“The repeat domain of tau with an FTDP-17 mutation (TauRD1K280) can be partially cracked into the F1 fragment [67].”
BackgroundPérez, M., Medina, M., Hernández, F., & Ávila, J. (2018) · BioMolecular Concepts · doi:10.1515/bmc-2018-0001 · Cited by 20
“Whereas full-length Tau is cleared by the proteasome system (46, 47), the mutated and truncated forms of Tau protein appear to be degraded by the autophagy-lysosomal pathway (48, 49).”
BackgroundFKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story
Chambraud, B., Byrne, C., Méduri, G., Baulieu, E. E., & Giustiniani, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031738 · Cited by 18
Autophagy in alzheimer disease pathogenesis and its therapeutic values
Angst, G., Jia, N., Esqueda, L. T., Fan, Y., Cai, Q., & Wang, C. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2471677 · Cited by 22
Sato, M., Ohta, T., Morikawa, Y., Konno, A., Hirai, H., Kurauchi, Y., Hisatsune, A., Katsuki, H., & Seki, T. (2020) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12649 · Cited by 17
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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