SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy
Sang-Won Min1*, Peter Dongmin Sohn1*, Yaqiao Li1, Nino Devidze1, Jeffrey R. Johnson2,3, Nevan J. Krogan1,3, Eliezer Masliah6, Sue-Ann Mok5, Jason E. Gestwicki5, Li Gan1,4 1Gladstone Institute of Neurological Disease, 2Gladstone Institute of Cardiovascular Disease, University of California, San Francisco; 3Department of Cellular and Molecular Pharmacology, 4Department of Neurology, 5Institute for Neurodegenerative Disease, Department of Pharmaceutical Chemistry, Weill Institute for Neurosciences, University of California, San Francisco; 6Department of Neuroscience, University of California San Diego, La Jolla, CA
Hyperacetylation of microtubule associated protein tau contributes to the formation of pathological tau aggregates and has been implicated in neurodegenerative disorders. Identifying deacetylating agents of tau that interfere with disease progression could offer important therapeutic insights. The NAD-dependent class III protein deacetylase Sirtuin 1 (SIRT1) is one of the major enzymes involved in the removal of acetyl groups from lysine residues of tau in vitro. However, little is known about the deacetylation mechanism of tau in vivo. To investigate the deacetylating activity of pathogenic tau by SIRT1, we depleted SIRT1 expression specifically in the brain of tauP301S transgenic mice and shown SIRT1 deficiency led to the exacerbation of premature mortality, synapse loss, and behavioral disinhibition in tauP301S mice. The trans-cellular spread of tau pathology has been used to stage the progression of tauopathies. The over expression of SIRT1 in the hippocampus by stereotaxic delivery of AAV virus encoded SIRT1 resulted in reduced acetylation of tau Lys174 in tauP301S, and attenuated the spreading of tau pathology into anatomically connected brain regions. Although our results have shown a protective role of SIRT1 in regulating disease progression, additional studies are needed to provide insights into molecular mechanisms of how SIRT1 mediates such a neuroprotective role and modulates propagation of tau pathology.
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