Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding

RNA-binding protein (RBP) dysfunction is a fundamental hallmark of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Abnormal neuronal excitability is also a conserved feature in ALS patients and disease models, yet little is known about how activity-dependent processes regulate RBP levels and functions. Mutations in the gene encoding the RBP Matrin 3 (MATR3) cause familial disease, and MATR3 pathology has also been observed in sporadic ALS, suggesting a key role for MATR3 in disease pathogenesis. Here, we show that glutamatergic activity drives MATR3 degradation through an NMDA receptor-, Ca2+-, and calpain-dependent mechanism. The most common pathogenic MATR3 mutation renders it resistant to calpain degradation, suggesting a link between activity-dependent MATR3 regulation and disease. We also demonstrate that Ca2+ regulates MATR3 through a nondegradative process involving the binding of Ca2+/calmodulin to MATR3 and inhibition of its RNA-binding ability. These findings indicate that neuronal activity impacts both the abundance and function of MATR3, underscoring the effect of activity on RBPs and providing a foundation for further study of Ca2+-coupled regulation of RBPs implicated in ALS and related neurological diseases.SignificanceHere, 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.