A nuclear BHMT-betaine methylation pathway provides neuroprotection in the cuprizone mouse model of multiple sclerosis
Singhal, N.K.1, Sternbach, S.1, Alkhayer, K.1, Shelestek, J.1, Popescu, D.1, Fleming, S.2, Clements, R.1, Bottiglieri, T.3, Freeman, E.1, McDonough, J.1
1Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, Ohio 44242. 2Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, 44272. 3Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas 75226. E-mail: firstname.lastname@example.org
We have found that the methionine metabolism enzyme betaine homocysteine methyltransferase (BHMT) is expressed in both rodent and human brain in the cortex, hippocampus, and cerebellum and is localized to the cytoplasm and nucleus in neurons. The BHMT catalyzed remethylation of homocysteine to methionine contributes to the synthesis of S-adenosylmethionine (SAM) which is the methyl donor for most methylation reactions in cells including histone methylation. Betaine however, is the methyl donor for BHMT catalyzed methylation reactions. Chromatin fractionation and co-immunoprecipitation studies reveal that BHMT is present in tight chromatin fractions in neurons where it interacts with the WDR5 subunit of the Set/MLL histone methyltransferase (HMT). We have also found that treating primary neuronal cultures with betaine increases Set/MLL HMT activity. ChIP-PCR shows that BHMT binds to promoter regions of genes involved in mitochondrial respiration. Supplementation with the methyl donor betaine increased levels of histone H3 trimethylation on lysine 4 (H3K4me3), enhanced neuronal respiration, and prevented axonal damage in the cuprizone toxic demyelinating mouse model of multiple sclerosis (MS). These data suggest that the methyl donor betaine may provide neuroprotection in relapse remitting phases of MS by supporting neuronal energetics during demyelinating events. Our data suggest that BHMT acts to synthesize a nuclear pool of the methyl donor SAM to increase H3K4me3 and activate transcriptional programs that support neuronal energetics.