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.

在多发性硬化症（MS）中，蛋氨酸代谢失调。甲基供体甜菜碱在MS脑中耗竭，与赖氨酸4（H3K4me3）上三甲基化的组蛋白H3水平变化和线粒体损伤有关。我们研究了在MS的cuprizone小鼠模型中替代这种耗尽的甜菜碱的效果。甜菜碱的补充可恢复铜酮小鼠的表观遗传控制并减轻其神经功能障碍。甜菜碱增加了甲基化潜力（SAM / SAH比），H3K4me3的水平，增强了神经元的呼吸作用，并防止了轴突损伤。我们显示甲基供体甜菜碱和甜菜碱高半胱氨酸甲基转移酶（BHMT）酶可以在细胞核中起作用，以修复表观遗传控制并激活神经保护性转录程序。ChIP-seq数据表明BHMT作用于染色质上以增加SAM / SAH比和局部组蛋白甲基转移酶活性，从而增加H3K4me3并激活支持神经元能量的基因表达。这些数据表明甲基供体甜菜碱可能在线粒体损伤损害轴突并导致残疾的MS中提供神经保护作用。