Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model

Acta Neuropathologica Communications

Lawrence Van Helleputte¹  Tom Jaspers¹  Matthieu Moisse¹  Elisabeth Rossaert¹  Eveliina Pollari¹  Ludo Van Den Bosch¹  Philip Van Damme¹  Katrien De Bock²  Matthew Jarpe³ 

[1] Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven – University of Leuven;Laboratory of Exercise and Health, Department of Health Sciences and Technology, ETH Zurich;Regenacy Pharmaceuticals Inc.;

关键词: Amyotrophic lateral sclerosis;    Neurodegeneration;    FUS;    Histone deacetylases;    HDAC inhibitors;    Epigenetics;   

DOI  :  10.1186/s40478-019-0750-2

来源: DOAJ

【 摘 要 】

Abstract Dysregulation of epigenetic mechanisms is emerging as a central event in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In many models of neurodegeneration, global histone acetylation is decreased in the affected neuronal tissues. Histone acetylation is controlled by the antagonistic actions of two protein families –the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). Drugs inhibiting HDAC activity are already used in the clinic as anti-cancer agents. The aim of this study was to explore the therapeutic potential of HDAC inhibition in the context of ALS. We discovered that transgenic mice overexpressing wild-type FUS (“Tg FUS+/+”), which recapitulate many aspects of human ALS, showed reduced global histone acetylation and alterations in metabolic gene expression, resulting in a dysregulated metabolic homeostasis. Chronic treatment of Tg FUS+/+ mice with ACY-738, a potent HDAC inhibitor that can cross the blood-brain barrier, ameliorated the motor phenotype and substantially extended the life span of the Tg FUS+/+ mice. At the molecular level, ACY-738 restored global histone acetylation and metabolic gene expression, thereby re-establishing metabolite levels in the spinal cord. Taken together, our findings link epigenetic alterations to metabolic dysregulation in ALS pathology, and highlight ACY-738 as a potential therapeutic strategy to treat this devastating disease.

【 授权许可】

Unknown