Identifying the role of translatome and therapeutic target in intractable epilepsy caused by brain somatic mutation in MTOR

Abstract

Brain somatic mutations confer genomic diversity in the human brain and cause neurodevelopmental disorders. Dysregulation of eukaryotic initiation factor 4E (eIF4E), which is a core translational regulator, is a common molecular hallmark in various neurological disorders. Individuals carrying inherited mutations in the mechanistic target of rapamycin (mTOR) or Ras/mitogen-activated protein kinase (MAPK) pathway, upstream activators of eIF4E, have abnormalities in translation and are prone to developing epilepsy, megalencephaly, autism spectrum disorder (ASD), brain tumor, and neuropshychiatric disorder. It has been hypothesized that brain somatic mutation that activates eIF4E is a potential culprit of neurological disorders. Here we report for the first time a mouse model with behavioral abnormalities including anxiety, defective sociability, deficits in repetitive behavior, and anhedonia caused by brain somatic mutation in MTOR. Recently, brain somatic activating mutations in MTOR have been identified as a major etiology of intractable epilepsy in patients with cortical malformations. However, the molecular genetic mechanism of how brain somatic mutations in MTOR cause intractable epilepsy has remained elusive. In this study, translational profiling of intractable epilepsy mouse models with brain somatic mutations and genome-edited cells revealed a novel translational dysregulation mechanism and mTOR activation–sensitive targets mediated by human MTOR mutations that lead to intractable epilepsy with cortical malformation. These mTOR targets were found to be regulated by novel mTOR-responsive 5′-UTR motifs, distinct from known mTOR inhibition–sensitive targets regulated by 5′ terminal oligopyrimidine motifs. Novel mTOR target genes were validated in patient brain tissues, and the mTOR downstream effector eIF4E was identified as a new therapeutic target in intractable epilepsy via pharmacological or genetic inhibition. We show that metformin, an FDA-approved eIF4E inhibitor, suppresses intractable epilepsy. However, there is no clinically relevant drug which specifically inhibits eIF4E in the brain. We found that antisense oligonucleotides (ASO) directed at eIF4E in the brain downregulated eIF4E and reversed the behavioral, neurophysiological, and bio-chemical abnormalities in mouse model with brain somatic mutation in MTOR. Altogether, the present study describes behavioral, neurophysiological, and biochemical abnormalities resulting from eIF4E dysregulation by mTOR pathway activation, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where eIF4E is dysregulated. Altogether, the present study describes translational dysregulation resulting from brain somatic mutations in MTOR, as well as the pathogenesis and potential therapeutic targets of intractable epilepsy.