title: The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.
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.
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA, James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Fontaine
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Mackenzie D
authors.initials: MD
authors.lastname: Martin
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen 37077, Germany, German Center for Neurodegenerative Diseases (DZNE), Göttingen 37077, Germany, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, Göttingen 37073, Germany and.
authors.forename: Elias
authors.initials: E
authors.lastname: Akoury
authors.affiliation: Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Assimon
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Borysov
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA, James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA, James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Sabbagh
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Cockman
authors.affiliation: Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen 37077, Germany, German Center for Neurodegenerative Diseases (DZNE), Göttingen 37077, Germany, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, Göttingen 37073, Germany and.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA, James A. Haley Veteran's Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA, cdickey@health.usf.edu.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009865:Oocytes; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000235:genetics / Q000628:therapy; D014981:Xenopus; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050883:HSC70 Heat-Shock Proteins; C054369:MAPT protein, human; D020033:Protein Isoforms; D016875:tau Proteins