Zhou et al. J. Clin. Invest. 129, 1756–1771 (2019)

Charcot-Marie-Tooth disease type 2A (CMT2A) is a neurodegenerative disease caused by mutations in the gene encoding mitofusin-2 (MFN2), a GTPase involved in mitochondrial dynamics. Although MFN2 is ubiquitously expressed, CMT2A preferentially affects the nervous system. According to a new study in mice, the low expression of MFN1 in the nervous system explains the tissue specificity of the disease.

The investigators generated transgenic mice that overexpress a mutated form of the human MFN2 protein specifically in neurons. Thy1.2–MFN2R94Q mice showed common clinical features of CMT2A, including sensorimotor deficits and vision loss, axonal degeneration as well as cytoplasmic and axonal mitochondrial accumulation. Crossing Thy1.2–MFN2R94Q mice with mice that overexpress human MFN1 in the nervous system (PrP-MFN1) rescued the CMT2A phenotype. Augmenting MFN1 in the nervous system could therefore be a viable strategy to treat CMT2A.