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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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“In this regard, Tau has been reported to contain two CMA targeting motifs obligatory for hsc70 binding and LAMP2A-mediated lysosomal degradation (Wang et al , 2009).”
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“For example, the aggregates generated by the overexpression of the tau repeat domain with an FTD-17 mutation (TauRD1K280) (252) as well as the proteolytically cleaved tau isoform D421 (Tau-C3) (260) are degraded by macroautophagy in cell models of tauopathy.”
BackgroundInfluentialTau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system
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“2008), and lysosomal processing influences tau aggregation and clearance in an inducible cellular model of tauopathy (Wang et al. 2009).”
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“The compromise in CMA is not limited to PD, as recent studies have revealed similar blockage of this pathway by certain mutant forms of Tau, the protein responsible for cellular toxicity in some tauopathies (Wang et al. 2009).”
ResultAutophagy and human disease: emerging themes
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“PD-related proteins a-synuclein, LRRK2, and UCH-L1 interfere with the assembly of the CMA translocation complex [35 ,36], whereas in tauopathies, pathogenic tau remains stuck inside the translocation complex [37] (Figure 2).”
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“(1) The aggregation-prone protein may perturb proteostasis by overexerting defenses against protein accumulation, notably proteasomal degradation or macroautophagy which are implicated in Tau clearance (Berger et al., 2006; Dickey et al., 2007; Carrettiero et al., 2009; Wang et al., 2009).”
BackgroundInfluentialAutophagy and disease: always two sides to a problem
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“As in the case of α-synuclein, the pathogenic forms of tau also organize into irreversible oligomeric structures at the lysosomal membrane that interfere with normal CMA, and in this case, also often result in destabilization of the lysosomal membrane and lysosomal enzyme leakage into the cytosol [48].”
BackgroundRodríguez-Navarro, J. A., Rodríguez, L., Casarejos, M. J., Solano, R. M., Gómez, A., Perucho, J., Cuervo, A. M., García de Yébenes, J., & Mena, M. A. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.05.014 · Cited by 298
“Recently, Wang et al. (2009) have described that both soluble tau and tau aggregates can be degraded by the autophagy–lysosomal system in a cell model of tauopathy.”
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
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“These events appear to be determinant toxicity effectors ( Johnson and Stooth-off, 2004 ; Min et al., 2015 ; Wang et al., 2009 ; Go¨tz et al., 2013 ; Kopeikina et al., 2012 ; Tian et al., 2013 ; Yanamandra et al., 2013 ; Cowan and Mudher, 2013 ), whereas tau tangles alone are not sufficient to…”
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“Previously, we showed that tau is degraded by autophagy in several inducible N2a cell lines overexpressing different tau constructs, as blocking autophagy resulted in elevated tau levels (Wang et al., 2009).”
BackgroundResultInfluentialImmunotherapy Targeting Pathological Tau Prevents Cognitive Decline in a New Tangle Mouse Model
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“…tau levels (Bendiske and Bahr, 2003), macroautophagy is likely involved in tau clearance (Berger et al., 2006; Hamano et al., 2008), and lysosomal processing has most recently been shown to influence tau aggregation and clearance in an inducible cellular model of tauopathy (Wang et al., 2009).”
BackgroundLysosome trafficking and signaling in health and neurodegenerative diseases
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“A mutant cleaved form of Tau, the protein that organizes into toxic fibrillar structures in Alzheimer’s disease (AD), is also delivered to lysosomes via CMA, and similar to the abnormal alpha-synucleins, mutant Tau fails to translocate properly [47].”
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“Like C9ORF72, tau binds to lysosomal membranes (Wang et al , 2009), and progranulin and its cleavage product granulin are localized inside the lysosome (Kao et al , 2017).”
A photoconvertible fluorescent reporter to track chaperone-mediated autophagy
Koga, H., Martínez‐Vicente, M., Macián, F., Verkhusha, V. V., & Cuervo, A. M. (2011) · Nature Communications · doi:10.1038/ncomms1393 · Cited by 226
“In some of these disorders, such as Parkinson’s disease or certain tauopathies, the pathogenic proteins that accumulate in the affected cells exert a direct toxic effect on CMA 13–15 .”
Ma, Q., Zuo, X., Yang, F., Ubeda, O. J., Gant, D. J., Alaverdyan, M., Teng, E., Hu, S., Chen, P., Maiti, P., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.393751 · Cited by 220
“HSPs are enriched at excitatory and inhibitory synapses and can regulate stabilization of synaptic receptor clusters (53, 54) as well as clearance of misfolded Tau (55).”
BackgroundChaperone-mediated autophagy at a glance
Kaushik, S., Bandyopadhyay, U., Sridhar, S., Kiffin, R., Martínez‐Vicente, M., Kon, M., Orenstein, S. J., Wong, E. S. P., & Cuervo, A. M. (2011) · Journal of Cell Science · doi:10.1242/jcs.073874 · Cited by 219
“The part of the protein that has already gained access to the lysosomal lumen undergoes sequential cleavage, which generates highly amyloidogenic peptides that oligomerize (Wang et al., 2009).”
BackgroundTau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease.
Chesser, A. S., Pritchard, S. M., & Johnson, G. V. W. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00122 · Cited by 219
Liu, Z., Li, T., Li, P., Wei, N., Zhao, Z., Liang, H., Ji, X., Chen, W., Xue, M., & Wei, J. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/352723 · Cited by 217
“Several studies have shown that dysfunction of the autophagy-lysosome system contributes to the formation of tau oligomers and insoluble aggregates [22, 173, 174].”
BackgroundClearance of Amyloid Beta and Tau in Alzheimer’s Disease: from Mechanisms to Therapy
Xin, S.-H., Tan, L., Cao, X., Yu, J.-T., & Tan, L. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9895-1 · Cited by 222
Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates
Park, H., Kang, J., & Lee, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093369 · Cited by 216
Zhang, W., Xu, C., Sun, J., Shen, H., Wang, J., & Yang, C. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.008 · Cited by 221
Autophagy in Alzheimer’s disease
Zare-shahabadi, A., Masliah, E., Johnson, G. V. W., & Rezaei, N. (2015) · Reviews in the Neurosciences · doi:10.1515/revneuro-2014-0076 · Cited by 204
Autophagy and Its Normal and Pathogenic States in the Brain
Yamamoto, A., & Yue, Z. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014149 · Cited by 204
Chaperone-mediated autophagy degrades mutant p53Preprint
Vakifahmetoglu-Norberg, H., Kim, M., Xia, H., Iwanicki, M., Ofengeim, D., Coloff, J. L., Pan, L., Ince, T. A., Kroemer, G., Brugge, J. S., et al. (2013) · Genes & Development · doi:10.1101/gad.220897.113 · Cited by 204
“Degradation of accumulated misfolded and aggregated proteins, such as mutant Tau and mutant Huntingtin (Htt) protein, has been demonstrated to occur through CMA (Wang et al. 2009; Bauer et al. 2010), while wild-type Htt is targeted to the UPS.”
BackgroundFatouros, C., Pir, G. J., Biernat, J., Koushika, S. P., Mandelkow�, E., Mandelkow, E., Schmidt, E., & Baumeister, R. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds190 · Cited by 201
“We generated transgenic strains expressing chromosomally integrated versions of the amyloidogenic F3DK280 fragment of human Tau [derived from the repeat domain of TauDK280 (16,17)] from the rab-3 promoter, to achieve pan-neuronal expression.”
BackgroundMethodTau phosphorylation affects its axonal transport and degradation
Rodríguez-Martín, T., Cuchillo‐Ibáñez, I., Noble, W. J., Nyenya, F., Anderton, B. H., & Hanger, D. P. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.03.015 · Cited by 211
“Our findings support and extend reports of the effects of 3-MA onwild type and phosphomutant tau in cells (Kim et al., 2011; Wang et al., 2009) and suggest that elevated phosphorylation could enhance tau degradation by the autophagic pathway.”
BackgroundResultThe Autophagy Lysosomal Pathway and Neurodegeneration
Finkbeiner, S. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a033993 · Cited by 196
“…protein response (UPR) and the ubiquitin proteasome system (UPS) are also critical (Webb et al. 2003; Keller et al. 2004; Kabuta et al. 2006; Wang et al. 2009, 2010a; Benbrook and Long 2012; Wang and Mandelkow 2012; Lee et al. 2013), and there is abundant evidence that there is cross talk…”
BackgroundUchiki, T., Weikel, K. A., Jiao, W., Shang, F., Caceres, A., Pawlak, D., Handa, J. T., Brownlee, M., Nagaraj, R., & Taylor, A. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2011.00752.x · Cited by 200
“Rather, they associate with the membrane fraction, akin to tau F1 (Wang et al., 2009).”
BackgroundThe fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush
Wegmann, S., Medalsy, I. D., Mandelkow�, E., & Müller, D. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212100110 · Cited by 201
“Therefore, one may speculate that Tau fibrils significantly change their adhesive properties when exposed to low pH during lysosomal degradation (30).”
BackgroundRoles of AMP-activated Protein Kinase in Alzheimer’s Disease
Cai, Z., Yan, L., Li, K., Quazi, S. H., & Zhao, B. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8173-2 · Cited by 198
“Induction of autophagy enhances the clearance of both soluble and aggregated forms of Ab and tau proteins in vivo and vitro (Wang et al. 2009).”
BackgroundBejarano, E., & Cuervo, A. M. (2010) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200909-102js · Cited by 200
Alzheimer's Disease: Redox Dysregulation As a Common Denominator for Diverse Pathogenic Mechanisms
Rommy von Bernhardi, M., & Eugenín, J. L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4082 · Cited by 193
“Autophagy has also been implicated in the modulation of tau level and fragmentation, and its inhibition elevates tau aggregation and toxicity (47, 687).”
BackgroundThe Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease
Ihara, Y., Morishima-Kawashima, M., & Nixon, R. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006361 · Cited by 190
“Incomplete charperone-mediated autophagy of tau generates fragments that aggregate and are cleared by macroautophagy (Wang et al. 2009).”
BackgroundKaminskyy, V. O., & Zhivotovsky, B. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.05.013 · Cited by 193
Autophagic and endo-lysosomal dysfunction in neurodegenerative disease
Malik, B. R., Maddison, D. C., Smith, G. A., & Peters, O. M. (2019) · Molecular Brain · doi:10.1186/s13041-019-0504-x · Cited by 187
“CMA contributes to the clearance of proteins associated with several neurodegenerative disorders [111, 112], with compelling evidence to suggest a role in the dopaminergic neuron loss seen in PD.”
BackgroundLaforin, the most common protein mutated in Lafora disease, regulates autophagy
Aguado, C., Sarkar, S., Korolchuk, V. I., Criado‐García, O., Vernia, S., Boya, P., Sanz, P., de Córdoba, S. R., Knecht, E., & Rubinsztein, D. C. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq190 · Cited by 188
Aβ Toxicity in Alzheimer's Disease
Cavallucci, V., D’Amelio, M., & Cecconi, F. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8251-3 · Cited by 179
“Both soluble and aggregated forms of tau are degraded by autophagy: autophagy inhibition, indeed, elevates tau aggregation and toxicity [134, 135], whereas autophagy induction by rapamycin decreases tau pathology [134, 136].”
Extracellular Monomeric Tau Protein Is Sufficient to Initiate the Spread of Tau Protein Pathology
Michel, C. H., Kumar, S., Pinotsi, D., Tunnacliffe, A., St. George-Hyslop, P., Mandelkow, E., Mandelkow, E.-M., Kaminski, C. F., & Kaminski Schierle, G. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.515445 · Cited by 165
“Thus, it is likely for nucleated exogenous Tau to be exposed to endogenous Tau that has been taken up by lysosomes (38) within the time frame of our experimental setup (72 h).”
Self-citationBowles, K. R., Silva, M. C., Whitney, K., Bertucci, T., Berlind, J. E., Lai, J. D., Garza, J. C., Boles, N. C., Mahali, S., Strang, K. H., et al. (2021) · Cell · doi:10.1016/j.cell.2021.07.003 · Cited by 175
Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice
Boimel, M., Grigoriadis, N., Lourbopoulos, A., Haber, E., Abramsky, O., & Rosenmann, H. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.05.010 · Cited by 174
Constitutive Upregulation of Chaperone-Mediated Autophagy in Huntington's Disease
Koga, H., Martínez‐Vicente, M., Arias, E., Kaushik, S., Sulzer, D., & Cuervo, A. M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3219-11.2011 · Cited by 178
“Protein aggregates can be removed by macroautophagy, one of the lysosomal pathways that contribute to the degradation of cytosolic material in lysosomes (Webb et al., 2003; Fornai et al., 2008; Wang et al., 2009).”
BackgroundXu, X., Sun, Y., Cen, X., Shan, B., Zhao, Q., Xie, T., Wang, Z., Hou, T., Xue, Y., Zhang, M., et al. (2021) · Protein & Cell · doi:10.1007/s13238-021-00858-3 · Cited by 171
“However, AD-associated forms of Tau aggregate and suppress CMA by binding to Lamp2a and disrupting its lysosomal translocation (Wang 2009).”
BackgroundUbiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications
Huang, Q., & Figueiredo‐Pereira, M. E. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0466-z · Cited by 177
“Studies addressing the role of aggregate formation on cell death rely, in many instances, on transfection and overexpression of wild type or mutant forms of proteins, such as tau [39], a-synuclein [40], parkin [41] or huntingtin [42], to list a few.”
Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers
Quinn, J. P., Corbett, N. J., Kellett, K. A. B., & Hooper, N. M. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-170959 · Cited by 170
“Cathepsin L can cleave the mutated aggregation-prone MT-binding domain fragment of tau (tau244-372 without K280; tauRD K) in Neuro-2A murine cells [67].”
BackgroundInfluential
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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