Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle

Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary sensory motor neuropathy, is caused by mutations of mitofusin-2 (MFN2). Mitofusin-2 is a GTPase required for fusion of mitochondrial outer membranes, repair of damaged mitochondria, efficient mitochondrial energetics, regulation of mitochondrial-endoplasmic reticulum calcium coupling and axonal transport of mitochondria. We knocked T105M MFN2 preceded by a loxP-flanked STOP sequence into the mouse Rosa26 locus to permit cell type-specific expression of this pathogenic allele. Crossing these mice with nestin-Cre transgenic mice elicited T105M MFN2 expression in neuroectoderm, and resulted in diminished numbers of mitochondria in peripheral nerve axons, an alteration in skeletal muscle fiber type distribution, and a gait abnormality.

Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy

“…Locomotion as well as gait defects are most evident in the CatWalk test (44), previously used in another CMT2A model (13). This test has revealed several parameters altered in CMT2A Tg mice, which highlight changes in the pressure and the surface of contact of the paw (spatial parameters) and in gait/posture (temporal parameter) and coordination.…”

“…Characterization of in vitro and in vivo models of the disease based on the expression of mutated MFN2 has led to substantial insights into the CMT2A pathophysiology (8)(9)(10)(11)(12). Multiple mouse models have been developed for CMT2A (8,(13)(14)(15); however, a transgenic line overexpressing MFN2 R94Q specifically in neurons (mitoCharc mice or CMT2A Tg) most closely mimics the late-onset CMT2A pathology (8). CMT2A Tg mice develop locomotor dysfunction from the age of 5 mo on, a pathologic effect associated at a late stage of the disease with the accumulation of mitochondria in small-caliber axons (8).…”

Structure, function, and regulation of mitofusin‐2 in health and disease

“…The development of novel experimental model systems remains key to define the mechanistic details of the multiple roles played by this molecule. Indeed, mouse and zebrafish models of CMT2A have provided crucial information on the importance of Mfn2 in normal physiology and disease (Detmer et al, 2008;Vettori et al, 2011;Chapman et al, 2013;Bannerman et al, 2016). Moreover, recent studies in small model organisms such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans have been instrumental in characterizing the role of mitochondria in neuronal health (Neumann & Hilliard, 2014;Rawson et al, 2014;Babic et al, 2015;Neumann et al, 2015;Melkov et al, 2016;Morsci et al, 2016;Yu et al, 2016).…”

Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans

“…Karle et al overcame this lethality with selective neuronal knockout of KIF5A, but insights into other cellular consequences such as muscle or NMJ phenotypes could not be made [61]. Mouse models have been generated for specific CMT2A mutations, including T105M and R94W, which have revealed important insights into the cellular mechanism of disease and therapeutic targets [6,[62][63][64][65]. However, further complicating our understanding of the disease is the finding of different patient-specific mutations having alternative (and sometimes opposing) effects on protein function [19,20].…”