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CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
Abstract
Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.
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“Induction of Hsp70 by geldanamycin promotes tau degradation both in vitro and in vivo, whereas deletion of CHIP increases the accumulation of phosphorylated tau and caspase-3 cleaved tau [167, 171].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [167]
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“The E3 ubiquitin ligase CHIP (carboxyl terminus of the Hsc70-interacting protein) is involved in polyubiquitination and degradation of p-tau (Petrucelli et al., 2004; Shimura et al., 2004).”
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“Reversible aggregation has been noted in other systems, such as the interaction of tau with CHIP [45,46].”
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“In AD brain, hsc70 is associated with neurofibrillary tangles (36) and has been described to interact with Tau (19).”
BackgroundInfluentialPromoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing
Boland, B., Yu, W. H., Corti, O., Mollereau, B., Henriques, A., Bézard, E., Pastores, G., Rubinsztein, D. C., Nixon, R. A., Duchen, M. R., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.109 · Cited by 566
Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
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“CHIP, a ubiquitin ligase, enhances the ubiquitination of the tau and also increases tau aggregation [72].”
BackgroundSmall heat shock proteins: molecular structure and chaperone function
Sun, Y., & MacRae, T. H. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5190-4 · Cited by 513
Regulation of proteasome activity in health and disease
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Mietelska‐Porowska, A., Wasik, U., Goras, M., Filipek, A., & Niewiadomska, G. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15034671 · Cited by 431
“Dickey et al. [194] showed that protein kinase Akt and ubiquitin ligase CHIP co-regulate tau degradation through coordinated interactions involving Hsp90.”
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Arakhamia, T., Lee, C. E., Carlomagno, Y., Kumar, M., Duong, D. M., Wesseling, H., Kundinger, S. R., Wang, K., Williams, D., Deture, M. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.01.027 · Cited by 411
Self-citationMicrotubule-associated protein tau in development, degeneration and protection of neurons
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17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration
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Aβ inhibits the proteasome and enhances amyloid and tau accumulation
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“More recently, it has been demonstrated that CHIP (carboxyl terminus of the Hsc70-interacting protein), a protein thought to be involved the process of quality-control of proteins as well as being an E3-ligase, regulates the degradation of tau and may prevent its aggregation (Murata et al., 2003, 2001; Petrucelli et a…”
BackgroundResultHistone deacetylase 6 interacts with the microtubule‐associated protein tau
Ding, H., Dolan, P. J., & Johnson, G. V. W. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05564.x · Cited by 387
“Existence of chaperones, ubiquitin ligases, and proteasome components in tau pathology clearly indicates that various cellular machineries might be actively utilized to cope with abnormal tau accumulation (Dou et al. 2003; Petrucelli et al. 2004; Fergusson et al. 1996).”
BackgroundThe Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases
Lackie, R. E., Maciejewski, A., Ostapchenko, V. G., Marques-Lopes, J., Choy, W., Duennwald, M. L., Prado, V. F., & Prado, M. A. M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00254 · Cited by 390
“A number of studies have shown that these hyperphosphorylated tau species can be recognized by Hsps and their co-chaperones, including Hsp27, Hsp70, CHIP, and αB crystalline, in order to repair malignant tau or proceed with its recycling (Dou et al., 2003; Dabir et al., 2004; Petrucelli et al., 2004; Shimura et al., 2…”
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“In contrast, other groups have reported that both mono- and polyubiquitination contribute to the formation of insoluble protein inclusions present in neurodegenerative diseases (96, 117) and that the induction of tau ubiquitination in cell cultures increases aggregation (102).”
BackgroundTau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system
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“, 1999); (3) proteins, such as chaperones and proteasomal proteins (Petrucelli et al., 2004; Xie and Guo, 2004); (4) enzymes, such as angiotensinconverting enzyme (ACE) (Hu et al.”
BackgroundInfluentialAccelerated neurodegeneration through chaperone-mediated oligomerization of tau
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“an Hsp90 cochaperone that can facilitate tau clearance through the proteasome (52, 53), increasing FKBP51 levels were able to displace CHIP from Hsp90 and preserve tau levels (Figure 6E).”
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Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52
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“A complex consisting of the E3 ligase CHIP (C terminus of Hsp70-interacting protein) in conjunction with several chaperones likely plays a role in maintaining tau in a functional conformation or directing it towards the degradation machinery 8, 44–46 .”
The Mechanistic Links Between Proteasome Activity, Aging and Agerelated Diseases
Sáez, I., & Vı́lchez, D. (2014) · Current Genomics · doi:10.2174/138920291501140306113344 · Cited by 331
“The ubiquitin ligase CHIP promotes tau degradation [122, 123].”
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Jana, N. R., Dikshit, P., Goswami, A., Kotliarova, S. E., Murata, S., Tanaka, K., & Nukina, N. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412042200 · Cited by 323
Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation
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“Recently, two groups have reported that tau is K63 polyubiquitinated by the E3-CHIP (Petrucelli et al. 2004; Shimura et al. 2004).”
BackgroundSmall Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein
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“CHIP and its binding protein Hsp70 can induce the ubiquitination and degradation of phosphorylated tau (Petrucelli et al., 2004; Shimura et al., 2004), deletion of CHIP leads to the accumulation of nonaggregated, hyperphosphorylated, as well as caspase-3-cleaved tau (Dickey et al., 2006).”
BackgroundCook, C. N., Carlomagno, Y., Gendron, T. F., Dunmore, J. H., Scheffel, K., Stetler, C. T., Davis, M., Dickson, D. W., Jarpe, M. B., Deture, M. A., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt402 · Cited by 325
“E1 (1:1000; human-specific tau antibody) was generated by our group against amino acid residues 19–33 within exon 1 of human tau (7,20,44).”
MethodSelf-citationHeat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases
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Alpha-synuclein and tau: teammates in neurodegeneration?
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“Heat shock proteins (HSPs) increase the association of tau with microtubules and regulate tau degradation, ubiquitination and phosphorylation [164,165].”
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“Parkin and tau interaction has been described after overexpression of both proteins (Petrucelli et al., 2004).”
Autophagic degradation of tau in primary neurons and its enhancement by trehalose
Krüger, U., Wang, Y., Kumar, S., & Mandelkow, E.-M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.11.009 · Cited by 297
“A number of reports have demonstrated that, in principle, tau can be degraded by the proteasome (David et al., 2002; Dickey et al., 2007; Petrucelli et al., 2004; Zhang et al., 2005).”
BackgroundImmunotherapy Targeting Pathological Tau Prevents Cognitive Decline in a New Tangle Mouse Model
Boutajangout, A., Quartermain, D., & Sigurdsson, E. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4363-10.2010 · Cited by 272
“Normal tau and at least certain species of nonaggregated hyperphosphorylated tau are likely degraded by the proteosome system as other soluble proteins (Petrucelli et al., 2004), whereas upon aggregation under pathological conditions, clearance through the autophagy/lysosomal system should be favored.”
BackgroundDisease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria
Cummins, N., Tweedie, A., Zuryn, S., Bertran‐Gonzalez, J., & Götz, J. (2019) · The EMBO Journal · doi:10.15252/embj.201899360 · Cited by 267
“In support of our data, Parkin and tau have also been demonstrated to co-immunoprecipitate in other cell types (Petrucelli et al , 2004; Moore et al , 2008).”
The ubiquitin‐proteasome system in Alzheimer's disease
Oddo, S. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00276.x · Cited by 267
“368 protein (CHIP), an E3 ubiquitin ligase that ubiquitinates tau for degradation by the proteasome [99, 100].”
BackgroundThe ubiquitin–proteasome pathway in Parkinson's disease and other neurodegenerative diseases
Ross, C. A., & Pickart, C. M. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.10.006 · Cited by 261
The Chaperone-associated Ubiquitin Ligase CHIP Is Able to Target p53 for Proteasomal Degradation
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“Our proaggregation mice displayed complete reversibility of the changes involving TauRD/ K280 [i.e., once the expression ceased, the protein disappeared in soluble and aggregated form within 6 weeks, consistent with proteasomal degradation (Petrucelli et al., 2004)].”
BackgroundMin, J.-N., Whaley, R. A., Sharpless, N. E., Lockyer, P., Portbury, A. L., & Patterson, C. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00296-08 · Cited by 256
“CHIP recognizes, ubiquitinates, and degrades unfolded chaperone substrates (9, 30, 34).”
BackgroundDickey, C. A., Yue, M., Lin, W.-L., Dickson, D. W., Dunmore, J. H., Lee, W. C., Zehr, C., West, G., Cao, S., Clark, A. M. K., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.0746-06.2006 · Cited by 248
“The antibodies used were as follows: rabbit polyclonal CHIP antibody (1:1000) (Petrucelli et al., 2004); rabbit polyclonal total tau and ubiquitin antibodies (1:1000; Dako, Carpinteria, CA); Tau5 and Tau-C3 [mouse monoclonal total tau antibody (1:1000) and a monoclonal antibody recognizing tau…”
BackgroundMethodResultInfluentialSelf-citationHsp70 – a master regulator in protein degradation
Fernández-Fernández, M. R., Gragera, M., Ochoa‐Ibarrola, L., Quintana‐Gallardo, L., & Valpuesta, J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12751 · Cited by 260
Tau Proteins and Tauopathies in Alzheimer’s Disease
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Tau in neurodegenerative disease
Gao, Y.-L., Wang, N., Sun, F.-R., Cao, X.-P., Zhang, W., & Yu, J.-T. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.04.23 · Cited by 222
“The carboxy-terminus of heat shock protein 70-interacting protein (CHIP), which is identified as the ubiquitin ligase, bonds with the phosphorylated tau, cooperates with ubiquitin and subsequently target tau to the proteasome (106).”
BackgroundPratt, W. B., Gestwicki, J. E., Osawa, Y., & Lieberman, A. P. (2014) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124332 · Cited by 244
Cellular and pathological functions of tau
Bravo, C. P., Naguib, S. A., & Gan, L. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00753-9 · Cited by 271
“Using various ubiquitin linkages and at distinct tau residues, three E3 ubiquitin ligases ubiq-uitylate tau: the C terminus of the Hsp70-interacting protein, TNF receptor-associated factor 6 and membrane-associated RING-CH7 74–78 , indicating diverse degradation mechanisms.”
Root, J. T., Merino, P., Nuckols, A., Johnson, M. A., & Kukar, T. L. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105360 · Cited by 243
Luo, H.-B., Xia, Y.-Y., Shu, X.-J., Liu, Z.-C., Feng, Y., Liu, X.-H., Yu, G., Yin, G., Xiong, Y.-S., Zeng, K., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417548111 · Cited by 236
“When the cells are exposed to the stresses, CHIP, a ubiquitin ligase that interacts directly with Hsp70/90, can induce tau ubiquitination and thus selectively reduce the level of detergent insoluble tau (17).”
BackgroundCHIP Suppresses Polyglutamine Aggregation and ToxicityIn VitroandIn Vivo
Miller, V. M., Nelson, R. F., Gouvion, C. M., Williams, A. J., Rodríguez-Lebrón, E., Harper, S. Q., Davidson, B. L., Rebagliati, M. R., & Paulson, H. L. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3001-05.2005 · Cited by 240
Dedmon, M. M., Christodoulou, J., Wilson, M. R., & Dobson, C. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413024200 · Cited by 246
Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability
Jinwal, U. K., Miyata, Y., Koren, J., Jones, J. R., Trotter, J. H., Chang, L., O’Leary, J. C., Morgan, D., Lee, D. C., Shults, C. L., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3345-09.2009 · Cited by 233
“Genetic evidence has previously suggested that increasing Hsp70 levels leads to increased binding to tau, which was necessary for CHIP-mediated ubiquitination and degradation (Petrucelli et al., 2004).”
BackgroundInfluentialAkt and CHIP coregulate tau degradation through coordinated interactions
Dickey, C. A., Koren, J., Zhang, Y.-J., Xu, Y.-F., Jinwal, U. K., Birnbaum, M. J., Monks, B., Sun, M., Cheng, J. Q., Patterson, C., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709180105 · Cited by 226
Self-citationTau 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
“However, another study, also using HEK cells and ubiquitin K48 and K63 mutants, demonstrated that in the presence of the E3 ligase CHIP, tau could be ubiquitylated by both K48 and K63 linkages (100).”
BackgroundTau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220
“show that CHIP overexpression can promote tau aggregation [285], and ubiquitination of tau by axotrophin significantly reduces the affinity of tau protein to microtubules [292].”
BackgroundUbiquitin–proteasome system and Parkinson's disease
Olanow, C. W., & McNaught, K. S. P. (2006) · Movement Disorders · doi:10.1002/mds.21013 · Cited by 219
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
“Overexpression of inducible HSP70 reduces soluble and insoluble Tau levels in aged mice (57).”
BackgroundIn vivo evidence of CHIP up‐regulation attenuating tau aggregation
Sahara, N., Murayama, M., Mizoroki, T., Urushitani, M., Imai, Y., Takahashi, R., Murata, S., Tanaka, K., & Takashima, A. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03272.x · Cited by 208
“Immunohistochemical studies found CHIP co-localized with tau-positive lesions in neurons and glia (Petrucelli et al. 2004).”
BackgroundInfluentialBeyer, K. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0104-6 · Cited by 216
“The functional signiWcance of -synuclein SUMO1 conjugation remains unknown, but the fact that -synuclein can be degraded by the proteasome through both ubiquitin dependent [6, 101, 114] and independent processes [124] suggests that a similar SUMOdependent competition is operative in both pathways.”
BackgroundAutophagy 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
“There are reports that have demonstrated UPS as a principal τ degradation system (David et al., 2002; Petrucelli et al., 2004; Zhang et al., 2005; Dickey et al., 2007).”
Wang, Y. P., Biernat, J., Pickhardt, M., Mandelkow�, E., & Mandelkow�, E. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703676104 · Cited by 216
Updates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 241
“On the other hand, Hsp70 and Hsp104 show inhibitory effects on tau seeding and aggregation [451, 452].”
BackgroundMechanisms of Suppression of α-Synuclein Neurotoxicity by Geldanamycin in Drosophila
Auluck, P. K., Meulener, M. C., & Bonini, N. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412106200 · Cited by 207
Al‐Ramahi, I., Lam, Y. C., Chen, H.-K., Gouyon, B., Zhang, M., Perez, A. M., Branco, J., de Haro, M., Patterson, C., Zoghbi, H. Y., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601603200 · Cited by 198
Tapia‐Rojas, C., Cabezas-Opazo, F., Deaton, C. A., Vergara, E. H., Johnson, G. V. W., & Quintanilla, R. A. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.005 · Cited by 207
“In vitro, overexpression studies showed that the E3 ubiquitin ligase CHIP (C-terminus of HSC70-interacting protein) interacts with Hsp70/90 and promotes ubiquitylation of tau (Petrucelli et al., 2004).”
BackgroundAllosteric Drugs: The Interaction of Antitumor Compound MKT-077 with Human Hsp70 Chaperones
Rousaki, A., Miyata, Y., Jinwal, U. K., Dickey, C. A., Gestwicki, J. E., & Zuiderweg, E. R. P. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.06.003 · Cited by 195
The 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
“…it has been reported that the E3 ligase CHIP (carboxyl terminus of the Hsc70-interacting protein) binds to tau and is involved in the degradation of abnormal forms of tau, including insoluble tau and hyperphosphorylated tau, coordinately with Hsp70 (Petrucelli et al. 2004; Dickey et al. 2006).”
BackgroundActivation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation
Wang, A. M., Miyata, Y., Klinedinst, S., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1140 · Cited by 186
Membrane Trafficking Pathways in Alzheimer's Disease
Rajendran, L., & Annaert, W. (2012) · Traffic · doi:10.1111/j.1600-0854.2012.01332.x · Cited by 171
“Phosphorylated tau is polyubiquitinated implying proteasomal breakdown as an important clearing mechanism (147, 148).”
BackgroundCHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3
Seo, J., Lee, E.-W., Sung, H., Seong, D., Dondelinger, Y., Shin, J., Jeong, M., Lee, H.-K., Kim, J.-H., Han, S. Y., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3314 · Cited by 182
STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy
Ferreira, J. V., Fofo, H., Bejarano, E., Bento, C. F., Ramalho, J. S., Girão, H., & Pereira, P. (2013) · Autophagy · doi:10.4161/auto.25190 · Cited by 187
Putcha, P., Danzer, K. M., Kranich, L. R., Scott, A., Silinski, M. A. R., Mabbett, S. R., Hicks, C. D., Veal, J. M., Steed, P. M., Hyman, B. T., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.158436 · Cited by 189
“Furthermore, Hsp90-CHIP complexes can target and selectively degrade phosphorylated tau-protein implicated in Alzheimer’s disease (Petrucelli et al., 2004), and Hsp90 inhibitors are also neuroprotective against toxicity caused by A aggregation (Ansar et al., 2007) as well as existing and induced…”
BackgroundThe Cochaperone BAG2 Sweeps Paired Helical Filament- Insoluble Tau from the Microtubule
Carrettiero, D. C., Hernández, I., Neveu, P. A., Papagiannakopoulos, T. Y., & Kosik, K. S. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.4660-08.2009 · Cited by 175
“The Tau protein triage system uses a complex consisting of the E3 ligase CHIP (C terminus of Hsp70-interacting protein) in conjunction with several chaperones to refold Tau or direct it toward the degradation machinery (Petrucelli et al., 2004; Shimura et al., 2004).”
BackgroundMechanisms tailoring the expression of heat shock proteins to proteostasis challenges
Boopathy, L. R. A., Jacob‐Tomas, S., Alecki, C., & Vera, M. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101796 · Cited by 183
Geldanamycin induces Hsp70 and prevents α-synuclein aggregation and toxicity in vitro
McLean, P. J., Klucken, J., Shin, Y., & Hyman, B. T. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.07.021 · Cited by 185
CHIP Targets Toxic α-Synuclein Oligomers for Degradation
Tetzlaff, J. E., Putcha, P., Outeiro, T. F., Ivanov, A., Berezovska, O., Hyman, B. T., & McLean, P. J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802283200 · Cited by 175
Poppek, D., Keck, S., Ermak, G., Jung, T., Stolzing, A., Ullrich, O., Davies, K. J. A., & Grune, T. (2006) · Biochemical Journal · doi:10.1042/bj20060463 · Cited by 174
Lee, G. S., & Leugers, C. J. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00004-7 · Cited by 173
Degradation of tau protein by autophagy and proteasomal pathways
Wang, Y., & Mandelkow, E. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120071 · Cited by 166
Statins reduce neuronal α‐synuclein aggregation in in vitro models of Parkinson’s disease
Bar‐On, P., Crews, L. A., Koob, A. O., Mizuno, H., Adame, A., Spencer, B. J., & Masliah, E. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05254.x · Cited by 169
“2005), immunoblot analysis was performed with neuronal cells fractionated into detergent soluble and insoluble fractions, as previously described with minor modifications (Petrucelli et al. 2004; Ho et al. 2005).”
Method
Metadata
- Authors
- Petrucelli, L.
- Affiliations
- Mayo Clinic in Florida (US)
- Corresponding author
- Petrucelli, L.
- ORCID
- Petrucelli, L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-01-28
- Volume
- 13
- Issue
- 7
- Pages
- 703-714
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2168079270
- Cited by
- 723
- References
- 41
- Citations by year
- 2026: 29 · 2025: 36 · 2024: 32 · 2023: 32 · 2022: 37 · 2021: 37 · 2020: 36 · 2019: 25 · 2018: 35 · 2017: 31 · 2016: 31 · 2015: 38 · 2014: 34 · 2013: 28 · 2012: 31
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS041816, R01-NS41816-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- CHIP, HSP70, tau protein, ubiquitination, protein degradation, tau aggregation, molecular chaperones, ubiquitin ligase, geldanamycin, heat shock factor 1, tauopathy, Alzheimer's disease, Parkinson's disease, proteasome
- MeSH terms
- Heat Shock Transcription Factors, Animals, Cell Line, Detergents, DNA-Binding Proteins, Genetic Vectors, Humans, Immunohistochemistry, Lac Operon, Models, Genetic, Mutation, Nuclear Proteins, Protein Binding, Quinones, Subcellular Fractions, Transcription Factors, Transfection, Blotting, Western, Benzoquinones, tau Proteins, Molecular Chaperones, HSP70 Heat-Shock Proteins, Transgenes, COS Cells, Ubiquitin, Drosophila Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Lactams, Macrocyclic, Immunoprecipitation, Mice
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