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The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

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dc.contributor.author Akoury, Elias
dc.contributor.author Martin, Mackenzie D.
dc.contributor.author Assimon, Victoria A.
dc.contributor.author Borysov, Sergiy
dc.date.accessioned 2019-03-22T08:24:24Z
dc.date.available 2019-03-22T08:24:24Z
dc.date.copyright 2015 en_US
dc.identifier.issn 1460-2083 en_US
dc.identifier.uri http://hdl.handle.net/10725/10252
dc.description.abstract The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks. en_US
dc.language.iso en en_US
dc.title The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 201900590 en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Human Molecular Genetics en_US
dc.journal.volume 24 en_US
dc.journal.issue 14 en_US
dc.article.pages 3971-3981 en_US
dc.keywords Heat-shock proteins 70 en_US
dc.keywords Microtubules en_US
dc.keywords Molecular chaperones en_US
dc.keywords Protein isoforms en_US
dc.keywords mapt gene en_US
dc.identifier.doi https://doi.org/10.1093/hmg/ddv135 en_US
dc.identifier.ctation Fontaine, S. N., Martin, M. D., Akoury, E., Assimon, V. A., Borysov, S., Nordhues, B. A., ... & Dickey, C. A. (2015). The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics. Human molecular genetics, 24(14), 3971-3981. en_US
dc.author.email elias.akoury@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://academic.oup.com/hmg/article/24/14/3971/2385773 en_US
dc.orcid.id https://orcid.org/0000-0001-5202-8935 en_US
dc.author.affiliation Lebanese American University en_US


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