Aberrant m6A methylation correlating with hippocampal pathology in multiple sclerosis

About This Grant

ABSTRACT Multiple sclerosis (MS) is an immune-mediated disease of the human central nervous system (CNS) affecting more than two million people worldwide. Among the spectrum of cognitive disability, memory dysfunction ranks primary among MS patients. Several studies have linked memory loss with hippocampal changes in MS patients. Investigating hippocampal pathology in MS patients, we reported demyelination of the hippocampus in greater than 60% of MS brains. Our previous studies found decreased axonal transport and loss of synapses following demyelination in both human and mouse hippocampus. It is however not clear how demyelination affects neuronal and synaptic changes. The field of epigenetics have been instrumental in changing our view about how factors, like DNA methylation, could change the expression and/or function of genes in several neurological diseases. N6-methyladenosine (m6A) is the most abundant and conserved co-transcriptional modification in eukaryotic RNAs controlled by m6A methyltransferases (m6A writers), recognized by m6A-binding proteins (m6A readers) and removed by the demethylases (m6A erasers). Balance between these three processes controls effective transcription and function of individual genes. Our preliminary results show a selective decrease in `m6A erasers' with concomitant increases in both `m6A writers' and `m6A readers' in MS hippocampal neurons. These abnormalities in the m6A pathway were supported by identification of several m6A methylated regions in genes belonging to synaptic structures. These results formed the basis of our hypothesis that “demyelination alters m6A methylation patterns in gene transcripts associated with synaptic plasticity and neuronal function in MS hippocampus”. This exploratory proposal will build on preliminary findings and use both human and mouse tissue to a) examine the levels and cellular identify of key m6A pathway members following hippocampal demyelination; and b) identify conserved m6A methylated residues and gene transcripts following hippocampal demyelination/remyelination. Our results will provide necessary data towards linking m6A modification, demyelination and neuronal function. Several drugs targeting the m6A pathway are of great interest in several diseases. We feel this study will pave the way for development of alternative interventions from the avenue of epigenetics to address neuronal dysfunction in MS.