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

Elisabeth Rossaert,Lawrence Van Helleputte,Tom Jaspers,Eveliina Pollari,Philip Van Damme,Matthew Jarpe,Katrien De Bock,Matthieu Moisse,Ludo Van Den Bosch

doi:10.1186/s40478-019-0750-2

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord, leading to the paralysis of voluntary muscles [51]
In line with our histological results, comparable amplitudes were measured at the gastrocnemius muscle in Tg Fused in sarcoma (FUS)+/+ mice and controls at pre-symptomatic age, but these were significantly reduced at end-stage, complying with gradual axonal loss (Fig. 1d)
To rule out the possibility that HDAC6 was mediating the therapeutic effect of ACY-738, we investigated whether the suppression of HDAC6 alone phenocopied the broad-acting Histone deacetylase (HDAC) inhibitor ACY-738, by combining genetic and pharmacological approaches

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord, leading to the paralysis of voluntary muscles [51]. The most prevalent genetic causes of ALS are mutations in the genes encoding superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and fused in. Mouse models manifesting the core symptoms of the disease, including a motor phenotype and motor neuron degeneration, remain crucial for the preclinical investigation of pathological mechanisms and novel therapeutic options. As all therapeutic strategies effective in the commonly used mutant SOD1 model subsequently failed in the clinic, other in vivo models to study ALS are urgently needed. One example is the PrP-hFUS-WT3 mouse model, which shows a strong ALS-like phenotype with severe motor neuron degeneration and a short

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