Control of neuronal cytoskeleton and intracellular transport machinery by arginine methylation

Neurons receive most excitatory synaptic inputs at dendritic spines, which are actin-enriched compartments that undergo dynamic changes during development and synaptic plasticity. Mushroom spines are crucial for memory storage, and their formation requires specific RNA-binding proteins (RBPs) that carry mRNAs along the microtubule from soma to dendrite and regulate their local translation. Deficiency of these RBPs may lead to over-production of immature filopodia that are associated with neurodevelopmental disorders. Arginine methylation is a well-known post-translational modification on histone and other nuclear proteins. Many RBPs in dendrite also contain RGG motifs which are hot spots of arginine methylation, suggesting that the importance of this post-translational modification may extend beyond its conventional function in gene transcription. Here I will describe the regulation of synaptic actin cytoskeleton by the arginine methyltransferase PRMT8, an unusual methyltransferase that is localized at neuronal synapses and up-regulated in the hippocampus during dendritic spine maturation. PRMT8 induces arginine methylation of G3BP1, a dendritic RBP, within the RGG motif and limits filopodia formation via the control of Rac1-PAK signaling, actin dynamics and mRNA translation. Interestingly, recent findings from us and others have revealed that besides RBPs, other transport proteins such as kinesin and huntingtin also undergo arginine methylation. Intracellular transport and cytoskeleton are therefore major targets modulated by arginine methylation during synapse development. © 2022 The Authors. Journal of Neurochemistry © 2022 International Society for Neurochemistry.