MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A

TLDR

Charcot‑Marie‑Tooth disease type 2A is a rare inherited neurodegenerative disorder causing progressive muscle weakness, motor deficits, and peripheral neuropathy, and is caused by MFN2 gene defects, yet remains incurable. The authors identified disease‑causing MFN2 residues and developed a class of MFN2‑agonist drugs. In mice, the small molecules restored mitochondrial fusion and activity in sciatic nerves, suggesting potential benefit for other mitochondrial trafficking disorders. Rocha et al.

Abstract

An innovative approach for a rare disease Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare, inherited neurodegenerative condition. Affected individuals develop severe progressive muscle weakness, motor deficits, and peripheral neuropathy. Although defects in the gene encoding mitofusin 2 (MFN2) are known to cause CMT2A, the disease remains incurable. Rocha et al. identified specific MFN2 residues contributing to the disease and developed a class of MFN2-agonist drugs. The small molecules restored mitochondrial fusion and activity in the sciatic nerves of mice; they may also help in other diseases linked to mitochondrial trafficking. Science , this issue p. 336