Is Nuclear mTOR Relevant for Neuronal Dysfunction?

Abstract

The mammalian target of rapamycin (mTOR) is a key regulator of neuronal development, metabolism, and plasticity, and its dysregulation is linked to many neurological disorders. Most studies have focused on cytoplasmic mTOR, yet mTOR is also present in the nucleus. In non-neuronal cells, nuclear mTOR has been linked to transcription, chromatin organization, and RNA metabolism. In neurons, its role remains largely unknown. Here, we present a focused Perspective on nuclear mTOR in the nervous system. We briefly summarize the best-established nuclear functions of mTOR, drawing mainly on evidence from non-neuronal cells. We then reanalyze published mTOR interactome datasets to assess whether these mechanisms may be relevant to neurons. Repeated links were observed to nuclear processes, particularly transcription, chromatin regulation, RNA processing, and DNA repair. Similar patterns were observed for gene sets associated with neurodevelopmental and neurodegenerative disorders. However, these associations are correlative and do not establish causality. Based on these findings, we propose a set of testable predictions and experimental approaches to directly examine nuclear mTOR function in neurons, including selective perturbation of its nuclear activity and analysis of gene expression and RNA processing. A key open question is whether nuclear mTOR has a functional role in neurons beyond its well-established cytoplasmic activities. This Perspective summarizes current evidence, highlights key gaps, and outlines directions for future studies on nuclear mTOR in neuronal function and disease.