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

doi:10.1016/j.celrep.2012.11.001

Cell Reports (Dec 2012)

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

DOI: https://doi.org/10.1016/j.celrep.2012.11.001
Journal volume & issue: Vol. 2, no. 6
pp. 1492 – 1497

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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