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

Abstract

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.

• Authors: Ahmed M Malik, Josephine J Wu, Christie A Gillies, Quinlan A Doctrove, Xingli Li, Haoran Huang, Elizabeth H M Tank, Vikram G Shakkottai, Sami Barmada
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 120 Issue 15 Pg. e2206217120 (04 11 2023) ISSN: 1091-6490 [Electronic] United States
• PMID: 37011198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Calcium
• Calmodulin
• Calpain
• RNA-Binding Proteins
• Nuclear Matrix-Associated Proteins
• MATR3 protein, human

Topics

• Humans
• Amyotrophic Lateral Sclerosis (metabolism)
• Calcium (metabolism)
• Calmodulin (genetics, metabolism)
• Calpain (genetics, metabolism)
• RNA-Binding Proteins (metabolism)
• Nuclear Matrix-Associated Proteins (metabolism)