Epitranscriptomic Regulation in Synaptic Plasticity, Aging and Neurodegeneration

Abstract

transcripts coding for synaptic proteins, although with more limited enrichment.Interestingly, despite decreased methylation, the protein levels of some of these transcripts were increased in synaptic compartments. The observed changes could be driven by an increased level of the m 6 A reader FTO at the synapse, or through the involvement of another RNA modification, N 6 ,2′-O-dimethyladenosine (m 6 Am). But more research focused on the role of m 6 A readers at the synapse will be needed to determine the exact mechanism of action.These results highlight the complexity and context-dependence of methylation marks and are a valuable addition to the growing evidence for the synaptic function of m 6 A methylation. More importantly, they represent some of the first studies that have looked for a link between the epitranscriptome landscape and how it can affect the state of synaptic transmission during cognitive enhancement and decline, interactions, becoming recently a target of interest in cancer research (Squires et al. 2012;Xue, Zhao, and Li 2020). Other modifications, although first identified decades ago, still remain elusive in their molecular functions, such is the case of N 1methyladenosine (m 1 A; Dunn 1961). m 1 A has long been known to modulate mainly tRNA structure, but it has only recently been identified in mRNAs as well (Dominissini et al. 2016). The function of m 1 A beyond ncRNAs is thought to involve the regulation of secondary structures and binding of mRNAs during translation, although not much is known about the extent of its involvement in other regulatory processes.The addition of m 6 A marks on the transcriptome is made possible by a group of proteins known as m 6 A "writers". Within this group are the proteins methyltransferase-like 3 (METTL3, now named Methyltransferase 3, N 6 -Adenosine-Methyltransferase Complex Catalytic Subunit) and methyltransferase-like 14 (METTL14, now named Methyltransferase 14, N 6 -Adenosine-Methyltransferase Subunit) which form the catalytic core of the m 6 A methyltransferase complex (mMC, J. ). These methyltransferases are sufficient to add m 6 A marks on target transcripts with considerable specificity. From them, the main catalytic function is performed by METTL3 while METLL14 acts primarily binding to the mRNA and ensuring correct METTL3 positioning (Bokar et al. 1994;. The catalytic core and the accessory, scaffolding and RNA-binding proteins (RBPs) associated with it are what is generally understood as the methyltransferase complex .Another key member of the mMC is WT1 associated protein (WTAP), an adaptor protein that binds both METTL3 and METTL14 and is responsible for their recruitment to active methylation sites . WTAP is also responsible for part of the specificity of targeted mRNAs, being able to directly bind to transcripts in the vicinity of m 6 A consensus sequences.More recently, additional proteins have been identified as accessory proteins of the m 6 A writer machinery and in certain literature they are considered components of the mMC (Moindrot et...