Your browser doesn't support javascript.
loading
Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding.
Malik, Ahmed M; Wu, Josephine J; Gillies, Christie A; Doctrove, Quinlan A; Li, Xingli; Huang, Haoran; Tank, Elizabeth H M; Shakkottai, Vikram G; Barmada, Sami.
Afiliação
  • Malik AM; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109.
  • Wu JJ; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109.
  • Gillies CA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109.
  • Doctrove QA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109.
  • Li X; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109.
  • Huang H; College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109.
  • Tank EHM; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109.
  • Shakkottai VG; Postbac Research Education Program, University of Michigan, Ann Arbor, MI 48109.
  • Barmada S; Department of Neurology, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A ; 120(15): e2206217120, 2023 04 11.
Article em En | MEDLINE | ID: mdl-37011198
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.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esclerose Lateral Amiotrófica Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esclerose Lateral Amiotrófica Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2023 Tipo de documento: Article