BIN1 modulation in vivo rescues dynamin-related myopathy.

Abstract

The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. DNM2 is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in Dnm2RW/+ and Dnm2RW/RW mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of Dnm2RW/+ mice and rescued the perinatal lethality and survival of Dnm2RW/RW mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.

• Authors: Valentina Maria Lionello, Christine Kretz, Evelina Edelweiss, Corinne Crucifix, Raquel Gómez-Oca, Nadia Messaddeq, Suzie Buono, Pascale Koebel, Xènia Massana Muñoz, Nadège Diedhiou, Belinda S Cowling, Marc Bitoun, Jocelyn Laporte
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 9 (03 01 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35217605 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 the Author(s). Published by PNAS.

Chemical References

• Adaptor Proteins, Signal Transducing
• BIN1 protein, human
• Nuclear Proteins
• Tumor Suppressor Proteins
• DNM2 protein, human
• Dynamin II

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Dynamin II (genetics, metabolism, physiology)
• Humans
• Mice
• Mice, Knockout
• Muscular Atrophy (physiopathology)
• Muscular Diseases (pathology)
• Nuclear Proteins (metabolism)
• Protein Binding
• Tumor Suppressor Proteins (metabolism)