Cullin-3–dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy
| Autor: | Kavya Tallapaka, Adam Bournazos, Jordan Blondelle, Jane T. Seto, Madison Clark, Jeffrey D. Singer, Majid Ghassemian, J. Laitila, Stephan Lange |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Neuromuscular Junction Muscle Proteins macromolecular substances Biology Myopathies Nemaline Congenital neuromuscular disorder Mice 03 medical and health sciences Myoblast fusion 0302 clinical medicine Nemaline myopathy Muscular Diseases medicine Animals Humans Myocyte Actinin Genetic Predisposition to Disease Ligase activity Muscle Skeletal Nemaline bodies Mice Knockout Muscle Weakness Myogenesis Gene Expression Regulation Developmental Membrane Proteins Skeletal muscle General Medicine Cullin Proteins medicine.disease 3. Good health Cell biology Disease Models Animal enzymes and coenzymes (carbohydrates) 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Mutation Research Article |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| Popis: | Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness, fiber atrophy, and presence of nemaline bodies within myofibers. However, understanding of the underlying pathomechanisms is lacking. Recently, mutations in KBTBD13, KLHL40, and KLHL41, three substrate adaptors for the E3 ubiquitin ligase Cullin-3, have been associated with early-onset nemaline myopathies. We hypothesized that deregulation of Cullin-3 and its muscle protein substrates may be responsible for disease development. Using Cullin-3–knockout mice, we identified accumulation of non-muscle α-actinins (ACTN1 and ACTN4) in muscles of these mice, which we also observed in patients with mutations in KBTBD13. Our data reveal that proper regulation of Cullin-3 activity and ACTN1 levels is essential for normal muscle and neuromuscular junction development. While ACTN1 is naturally downregulated during myogenesis, its overexpression in C2C12 myoblasts triggered defects in fusion, myogenesis, and acetylcholine receptor clustering — features that we characterized in Cullin-3–deficient mice. Taken together, our data highlight the importance of Cullin-3–mediated degradation of ACTN1 for muscle development, and indicate what is to our knowledge new pathomechanism for the etiology of myopathies seen in Cullin-3–knockout mice and patients with nemaline myopathy. |
| Databáze: | OpenAIRE |
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