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Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-73...

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Autores principales: Burg, Thibaut, Rossaert, Elisabeth, Moisse, Matthieu, Van Damme, Philip, Van Den Bosch, Ludo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541517/
https://www.ncbi.nlm.nih.gov/pubmed/34681883
http://dx.doi.org/10.3390/ijms222011224
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author Burg, Thibaut
Rossaert, Elisabeth
Moisse, Matthieu
Van Damme, Philip
Van Den Bosch, Ludo
author_facet Burg, Thibaut
Rossaert, Elisabeth
Moisse, Matthieu
Van Damme, Philip
Van Den Bosch, Ludo
author_sort Burg, Thibaut
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.
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spelling pubmed-85415172021-10-24 Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis Burg, Thibaut Rossaert, Elisabeth Moisse, Matthieu Van Damme, Philip Van Den Bosch, Ludo Int J Mol Sci Article Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases. MDPI 2021-10-18 /pmc/articles/PMC8541517/ /pubmed/34681883 http://dx.doi.org/10.3390/ijms222011224 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Burg, Thibaut
Rossaert, Elisabeth
Moisse, Matthieu
Van Damme, Philip
Van Den Bosch, Ludo
Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis
title Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis
title_full Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis
title_fullStr Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis
title_full_unstemmed Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis
title_short Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis
title_sort histone deacetylase inhibition regulates lipid homeostasis in a mouse model of amyotrophic lateral sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541517/
https://www.ncbi.nlm.nih.gov/pubmed/34681883
http://dx.doi.org/10.3390/ijms222011224
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