GSE116863
Restoring Mitofusin balance in the nervous system prevents axonal degeneration in a CMT2A mouse model
MFN2 is a mitochondrial outer membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2 (which cause Charcot-Marie-Tooth disease type 2A) primarily affect the nervous system.  We generated a transgenic mouse model of CMT2A which developed severe early-onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria labeled for degradation.  Mutant MFN2R94Q had a dominant negative effect on mitochondrial fusion if MFN1 was absent or at low levels, as in neurons.  Finally we found that augmenting the level of MFN1 in the nervous system in vivo led to rescue of all phenotypes in mutant MFN2R94Q expressing mice.  These data demonstrate that the MFN1:MFN2 ratio is a key determinant of tissue specificity in CMT2A, and indicates that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease. Overall design: Comparing lumbar spinal cord transcription profiles from MFN2-R94Q mice (n=3), MFN2-R94Q:MFN1 mice (n=5), and nontransgenic control mice (n=3)