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

Autor: Tom Jaspers, Eveliina Pollari, Elisabeth Rossaert, Matthew Jarpe, Ludo Van Den Bosch, Matthieu Moisse, Philip Van Damme, Katrien De Bock, Lawrence Van Helleputte
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
TRICHOSTATIN-A
Hydroxamic Acids
lcsh:RC346-429
AMYOTROPHIC-LATERAL-SCLEROSIS
Histones
Mice
Random Allocation
0302 clinical medicine
Histone deacetylases
HDAC inhibitors
HDAC6 INHIBITORS
Histone Acetyltransferases
Amyotrophic lateral sclerosis
Neurodegeneration
FUS
Epigenetics
Metabolism
biology
GENE ONTOLOGY
Acetylation
DEACETYLASE INHIBITOR
3. Good health
Histone
SKELETAL-MUSCLE
Female
Life Sciences & Biomedicine
medicine.drug
Mice
Transgenic
Context (language use)
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
VALPROIC ACID
medicine
Animals
Humans
Metabolomics
lcsh:Neurology. Diseases of the nervous system
FRONTOTEMPORAL LOBAR DEGENERATION
Science & Technology
Research
Neurosciences
medicine.disease
Histone Deacetylase Inhibitors
Disease Models
Animal
Pyrimidines
030104 developmental biology
Trichostatin A
biology.protein
Cancer research
RNA-Binding Protein FUS
SODIUM PHENYLBUTYRATE
MOTOR-NEURON DEGENERATION
Neurosciences & Neurology
Neurology (clinical)
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica Communications, 7 (1)
Acta Neuropathologica Communications
Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-19 (2019)
ISSN: 2051-5960
DOI: 10.1186/s40478-019-0750-2
Popis: 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.
Acta Neuropathologica Communications, 7 (1)
ISSN:2051-5960
Databáze: OpenAIRE
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