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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 Dnm2 RW/+ and Dnm2 RW/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 Dnm2 RW/+ mice and rescued the perinatal lethality and survival of Dnm2 RW/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.
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Contributor : Jocelyn Laporte Connect in order to contact the contributor
Submitted on : Friday, March 18, 2022 - 1:00:59 PM
Last modification on : Friday, November 18, 2022 - 11:08:57 AM

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Valentina Maria Lionello, Christine Kretz, Evelina Edelweiss, Corinne Crucifix, Raquel Gómez-Oca, et al.. BIN1 modulation in vivo rescues dynamin-related myopathy. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119 (9), ⟨10.1073/pnas.2109576119⟩. ⟨hal-03613287⟩



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