The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington’s Disease Mouse Models
Vanita Chopra,
Luisa Quinti,
Jinho Kim,
Lorraine Vollor,
K. Lakshmi Narayanan,
Christina Edgerly,
Patricia M. Cipicchio,
Molly A. Lauver,
Soo Hyuk Choi,
Richard B. Silverman,
Robert J. Ferrante,
Steven Hersch,
Aleksey G. Kazantsev
Affiliations
Vanita Chopra
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA
Luisa Quinti
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA
Jinho Kim
Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, PA 15213, USA
Lorraine Vollor
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA
K. Lakshmi Narayanan
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA
Christina Edgerly
Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, PA 15213, USA
Patricia M. Cipicchio
Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, PA 15213, USA
Molly A. Lauver
Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, PA 15213, USA
Soo Hyuk Choi
Department of Chemistry, Department of Molecular Bioscience, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA
Richard B. Silverman
Department of Chemistry, Department of Molecular Bioscience, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA
Robert J. Ferrante
Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, PA 15213, USA
Steven Hersch
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA
Aleksey G. Kazantsev
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA
Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson’s disease and Huntington’s disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.
