Role of Mettl3-dependent RNA m6A dysregulation in Alzheimer's disease

Case Western Reserve University, Cleveland OH

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Abstract

PROJECT SUMMARY/ABSTRACT As a complex and multifactorial disease, a combination of genetics, environmental and lifestyle factors affect ones’ risk of developing AD through complex transcriptional and translational changes in the gene expression in AD brain, however, the mechanisms underlying these changes remain elusive. Analogous to DNA and histone modifications, RNA modifications could also lead to alterations in gene expression which allows extra layers of regulation of gene expression. N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNAs which regulates RNA stability, processing, localization, translation. It is involved in various biological processes including mitochondrial function, synaptic function and cognitive function, but the potential role of RNA m6A modification in aging and age-related neurodegenerative diseases including AD is largely unexplored. Studies from my group and several other groups demonstrated METTL3-m6A dysregulation is an early event during the course of AD. METTL3 knockdown in the hippocampus caused AD-related cognitive deficits and neurodegeneration while METTL3 overexpression rescued AβO-induced neuronal/synaptic and cognitive/behavioral deficits, suggesting a critical role of METTL3-m6A dysregulation in the pathogenesis of AD. mRNA of many AD-related genes contain m6A suggesting that METTL3-dependent m6A modification likely have impacts on multiple aspects related to AD. Given that mitochondrial dysfunction plays a critical role in the pathogenesis of AD, it is of particular interest to note that methylation profiling identified multiple m6A sites in mRNAs of key regulators of mitochondrial functions including those involved in mitochondrial biogenesis (i.e., PGC1α and TFAM) and mitochondrial dynamics (i.e., Mfn2 and DLP1). Indeed, METTL3 knockdown caused mitochondrial fragmentation and dysfunction likely through modulation of PGC1α and Mfn2 expression which could contribute to Aβ oligomers-induced mitochondrial dysfunction. Based on these studies, we hypothesized that reduced METTL3-m6A signaling modulates the expression of mitochondrial regulators and contributes to mitochondrial dysfunction and the pathogenesis of AD. Therefore, METTL3 overexpression rescues m6A signaling and mitochondrial gene expression and function and alleviates AD-related deficits. We will determine the mechanisms underlying METTL3 reduction in AD and explore whether and how reduced METTL3 mediates toxic effects of AβO on mitochondrial biogenesis/dynamics and function in AD. Novel animal models with METTL3 overexpression in the forebrain will be crossed with AD transgenic mouse models and carefully characterized. The successful completion of this study will provide novel mechanistic insights into changes in gene expression in AD and will likely establish METTL3-m6A signaling as a promising therapeutic target for drug development in AD, which also have implications of studying other neurodegenerative disorders and aging in general.