1. BIN1 modulation in vivo rescues dynamin-related myopathy.
- Author
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Lionello VM, Kretz C, Edelweiss E, Crucifix C, Gómez-Oca R, Messaddeq N, Buono S, Koebel P, Massana Muñoz X, Diedhiou N, Cowling BS, Bitoun M, and Laporte J
- Subjects
- Animals, Dynamin II genetics, Dynamin II metabolism, Humans, Mice, Mice, Knockout, Protein Binding, Adaptor Proteins, Signal Transducing metabolism, Dynamin II physiology, Muscular Atrophy physiopathology, Muscular Diseases pathology, Nuclear Proteins metabolism, Tumor Suppressor Proteins metabolism
- 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 Dnm2
RW/+ 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., Competing Interests: Competing interest statement: B.S.C. and J.L. are co-founders of Dynacure. R.G.-O., S.B., and B.S.C. are currently employed by Dynacure., (Copyright © 2022 the Author(s). Published by PNAS.)- Published
- 2022
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