Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis
| Autor: | Kholoud Alkhayer, Daniela C. Popescu, Naveen Kumar Singhal, Alyx Weaver, Sheila Fleming, Robert Clements, Jennifer McDonough, John Shelestak, Teodoro Bottiglieri, Ernest J. Freeman, Sarah Sternbach, Brandi Wasek |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Multiple Sclerosis Methionine metabolism Cell Respiration Lysine Biology Mitochondrion Epigenesis Genetic Rats Sprague-Dawley Cuprizone Mice 03 medical and health sciences chemistry.chemical_compound Histone H3 0302 clinical medicine Betaine medicine Animals Epigenetics Molecular Biology Cells Cultured Neurons Multiple sclerosis Chromatin Assembly and Disassembly medicine.disease Mitochondria Rats Cell biology Histone Code Mice Inbred C57BL 030104 developmental biology Betaine-Homocysteine S-Methyltransferase chemistry 030220 oncology & carcinogenesis H3K4me3 lipids (amino acids peptides and proteins) sense organs Research Paper |
| Zdroj: | Epigenetics |
| ISSN: | 1559-2308 1559-2294 |
| Popis: | Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability. |
| Databáze: | OpenAIRE |
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