BIN1 reduction ameliorates <i>DNM2</i>-related Charcot-Marie-Tooth neuropathy.

Abstract

Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, manifests as progressive muscle weakness and peripheral nerve defects. Dominant mutations in <i>DNM2</i>, encoding the large GTPase dynamin 2, result in CMT without any suggested therapeutic strategy. Different dominant mutations in <i>DNM2</i> 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 <i>Dnm2</i>^K562E/+ mouse carrying the most common <i>DNM2</i>-CMT mutation. Conversely, whole-body reduction of <i>Bin1</i> expression level, through the generation of <i>Dnm2</i>^K562E/+ mice with heterozygous loss of BIN1, restored motor performance and ameliorated muscle organization and structural defects of 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 <i>DNM2</i>-CMT mutant, and a normalization of integrin localization in muscle. Overall, this study highlights BIN1 as a modifier of <i>DNM2</i>-CMT, and its reduction as a potential therapeutic strategy. It also revealed an opposite pathological mechanism and inverse therapeutic concepts for <i>DNM2</i>-CMT peripheral neuropathy versus <i>DNM2</i>-CNM myopathy.