Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding
| Autor: | 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 |
|---|---|
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 120 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2206217120 |
| Popis: | 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-, Ca 2+ -, 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 Ca 2+ regulates MATR3 through a nondegradative process involving the binding of Ca 2+ /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 Ca 2+ -coupled regulation of RBPs implicated in ALS and related neurological diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|