Lionello, Valentina Maria;
Kretz, Christine;
Edelweiss, Evelina;
Crucifix, Corinne;
Gomez-Oca, Raquel;
Messaddeq, Nadia;
Buono, Suzie;
... Laporte, Jocelyn; + view all
(2022)
BIN1 modulation in vivo rescues dynamin-related myopathy.
PNAS (Proceedings of the National Academy of Sciences)
, 119
(9)
, Article e2109576119. 10.1073/pnas.2109576119.
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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.
| Type: | Article |
|---|---|
| Title: | BIN1 modulation in vivo rescues dynamin-related myopathy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.2109576119 |
| Publisher version: | https://doi.org/10.1073/pnas.2109576119 |
| Language: | English |
| Additional information: | Copyright © 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), https://creativecommons.org/licenses/by-nc-nd/4.0/. |
| Keywords: | Congenital myopathy; membrane remodeling; gene therapy; dynamin; amphiphysin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10204029 |
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