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Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice.

ABSTRACT: The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.

SUBMITTER: Ferrante RJ

PROVIDER: S-EPMC6740577 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice.

Ferrante Robert J RJ Kubilus James K JK Lee Junghee J Ryu Hoon H Beesen Ayshe A Zucker Birgit B Smith Karen K Kowall Neil W NW Ratan Rajiv R RR Luthi-Carter Ruth R Hersch Steven M SM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20031001 28

The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed ...[more]

PMID: 14561870

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Project description:Short-chain fatty acids (SCFAs, especially butyric acid) have been demonstrated to play a promising role in the development of autism spectrum disorders (ASD). Recently, the hypothalamic-pituitary-adrenal (HPA) axis is also suggested to increase the risk of ASD. However, the mechanism underlying SCFAs and HPA axis in ASD development remains unknown. Here, we show that children with ASD exhibited lower SCFA concentrations and higher cortisol levels, which were recaptured in prenatal lipopolysaccharide (LPS)-exposed rat model of ASD. These offspring also showed decreased SCFA-producing bacteria and histone acetylation activity as well as impaired corticotropin-releasing hormone receptor 2 (CRHR2) expression. Sodium butyrate (NaB), which can act as histone deacetylases inhibitors, significantly increased histone acetylation at the CRHR2 promoter in vitro and normalized the corticosterone as well as CRHR2 expression level in vivo. Behavioral assays indicated ameliorative effects of NaB on anxiety and social deficit in LPS-exposed offspring. Our results imply that NaB treatment can improve ASD-like symptoms via epigenetic regulation of the HPA axis in offspring; thus, it may provide new insight into the SCFA treatment of neurodevelopmental disorders like ASD. IMPORTANCE Growing evidence suggests that microbiota can affect brain function and behavior through the "microbiome-gut-brain'' axis, but its mechanism remains poorly understood. Here, we show that both children with autism and LPS-exposed rat model of autism exhibited lower SCFA concentrations and overactivation of HPA axis. SCFA-producing bacteria, Lactobacillus, might be the key differential microbiota between the control and LPS-exposed offspring. Interestingly, NaB treatment contributed to the regulation of HPA axis (such as corticosterone as well as CRHR2) and improvement of anxiety and social deficit behaviors in LPS-exposed offspring. The potential underlying mechanism of the ameliorative effect of NaB may be mediated via increasing histone acetylation to the CRHR2 promoter. These results enhance our understanding of the relationship between the SCFAs and the HPA axis in the development of ASD. And gut microbiota-derived SCFAs may serve as a potential therapeutic agent to neurodevelopmental disorders like ASD.

Dataset Information

Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice.

Publications

Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice.

Similar Datasets

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