LAUSR

Significance Here, we define the molecular pathways responsible for regulating the abundance of Matrin 3 (MATR3), an RNA-binding protein with integral ties to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We show that the excitatory neurotransmitter glutamate triggers MATR3 inactivation and degradation in vitro and ex vivo. Subsequent experiments detail a signal transduction pathway controlling not just MATR3 abundance but also its ability to recognize RNA. These observations have significant implications for physiological MATR3 regulation and clarify the mechanism by which pathogenic MATR3 mutations compromise such regulation. Together with our prior work cataloging the sensitivity of neurons to changes in MATR3 abundance, these data detail a pathophysiological cascade contributing to neurodegeneration in familial ALS and FTD due to MATR3 mutations.