BIN1 reduction ameliorates DNM2-related Charcot-Marie-Tooth neuropathy

• 成果类型: Article
• 署名作者: Goret, Marie; Thomas, Morgane; Edelweiss, Evelina; Messaddeq, Nadia; Laporte, Jocelyn
• 署名单位: Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15302
• DOI: 10.1073/pnas.2419244122
• 发表日期: 2025-03-11
• 关键词: dynamin 2; centronuclear myopathy; clinical management; amphiphysin-2 bin1; crystal-structure; mutations; domain; endocytosis; physiology; spectrum

摘要

Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, manifests as progressive muscle weakness and peripheral nerve defects. Dominant mutations in DNM2, encoding the large GTPase dynamin 2, result in CMT without any suggested therapeutic strategy. Different dominant mutations in DNM2 also cause centronuclear myopathy (CNM), and increasing BIN1 (amphiphysin 2), an endogenous modulator of DNM2, rescued CNM in mice. Here, we found that increasing BIN1 level exacerbated the phenotypes of the Dnm2K562E/+ mouse carrying the most common DNM2-CMT mutation. Conversely, whole-body reduction of Bin1 expression level, through the generation of Dnm2K562E/+ mice with heterozygous loss of BIN1, restored motor performance and ameliorated muscle organization and structural defects peripheral nerves. The rescue of motor defects was maintained at least up to 1 y of age. BIN1 inhibited the GTPase activity of DNM2, and the rescue was driven by an increased activity of the K562E DNM2-CMT mutant, and a normalization of integrin localization in muscle. Overall, this study highlights BIN1 as a modifier of DNM2-CMT, and reduction as a potential therapeutic strategy. It also revealed an opposite pathological mechanism and inverse therapeutic concepts for DNM2-CMT peripheral neuropathy versus DNM2-CNM myopathy.