Dataset Information

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

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.

SUBMITTER: Rossaert E

PROVIDER: S-EPMC6612190 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Rossaert Elisabeth E Pollari Eveliina E Jaspers Tom T Van Helleputte Lawrence L Jarpe Matthew M Van Damme Philip P De Bock Katrien K Moisse Matthieu M Van Den Bosch Ludo L

Acta neuropathologica communications 20190705 1

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 ...[more]

PMID: 31277703

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Project description:Craniometaphyseal dysplasia (CMD), a rare genetic bone disorder, is characterized by lifelong progressive thickening of craniofacial bones and metaphyseal flaring of long bones. The autosomal dominant form of CMD is caused by mutations in the progressive ankylosis gene ANKH (mouse ortholog Ank), encoding a pyrophosphate (PPi) transporter. We previously reported reduced formation and function of osteoblasts and osteoclasts in a knockin (KI) mouse model for CMD (AnkKI/KI) and in CMD patients. We also showed rapid protein degradation of mutant ANK/ANKH. Mutant ANK protein displays reduced PPi transport, which may alter the inorganic phosphate (Pi) and PPi ratio, an important regulatory mechanism for bone mineralization. Here we investigate whether reducing dietary Pi intake can ameliorate the CMD-like skeletal phenotype by comparing male and female Ank+/+ and AnkKI/KI mice exposed to a low (0.3%) and normal (0.7%) Pi diet for 13 weeks from birth. Serum Pi and calcium (Ca) levels were not significantly changed by diet, whereas PTH and 25-hydroxy vitamin D (25-OHD) were decreased by low Pi diet but only in male Ank+/+ mice. Importantly, the 0.3% Pi diet significantly ameliorated mandibular hyperostosis in both sexes of AnkKI/KI mice. A tendency of decreased femoral trabeculation was observed in male and female Ank+/+ mice as well as in male AnkKI/KI mice fed with the 0.3% Pi diet. In contrast, in female AnkKI/KI mice the 0.3% Pi diet resulted in increased metaphyseal trabeculation. This was also the only group that showed increased bone formation rate. Low Pi diet led to increased osteoclast numbers and increased bone resorption in all mice. We conclude that lowering but not depleting dietary Pi delays the development of craniofacial hyperostosis in CMD mice without severely compromising serum levels of Pi, Ca, PTH, and 25-OHD. These findings may have implications for better clinical care of patients with CMD. © 2020 American Society for Bone and Mineral Research.

Dataset Information

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

Publications

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

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