Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A.

Antonietta Franco,Gerald W Dorn,Xiawei Dang,Emily K Walton,Andrew S Yoo,Cindy Ly,Joshua N Ho,Timothy M Miller,Michael E Shy,Barbara Zablocka,Robert H Baloh

doi:10.7554/elife.61119

Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.

Highlights

Charcot–Marie-Tooth disease (CMT) describes a family of genetically diverse and clinically heterogeneous peripheral neuropathies (Fridman et al, 2015)
Compared to neurons reprogrammed from individuals with no evident disease at the time of sampling and who had none of the tested mitofusin 2 (MFN2) mutations by Sanger sequencing (‘normal’), all four Charcot–Marie-Tooth disease type 2A (CMT2A) motor neuron lines exhibited fragmented mitochondria that is a consequence of impaired fusion in this context Franco et al, 2016; accompanying mitochondrial depolarization reflected characteristic functional impairment (Figure 1c; Crowley et al, 2016)
These preclinical studies show that activating endogenous normal mitofusins can improve stable neuromuscular dysfunction caused by a CMT2A MFN2 mutant

Summary

Introduction

Charcot–Marie-Tooth disease (CMT) describes a family of genetically diverse and clinically heterogeneous peripheral neuropathies (Fridman et al, 2015). Dang et al tested the drug in the mice with a CMT2A mutation and found that it could stimulate nerves to regrow and so reverse muscle loss and weakness. This is the first time scientists have succeeded to reverse the effects of CMT2A in nerve cells of mice and humans. These drugs will still need to go through extensive testing in clinical trials before being made widely available to patients. Reversal of pre-existing CMT2A neuromuscular degeneration in vivo has not previously been achieved by any means, and provides a powerful rationale for advancing mitofusin activators to first in human trials

Results

Discussion

Materials and methods

Funding Funder National Institutes of Health