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Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A

Arnaud, Estelle
Médard, Jean-Jacques
Poirot, Olivier
Chrast, Roman
Published in Brain. 2010, vol. 133, no. Pt 5, p. 1460-1469
Abstract Charcot-Marie-Tooth disease type 2A is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene. Mitofusin 2 encodes a mitochondrial outer membrane protein that participates in mitochondrial fusion in mammalian cells. How mutations in this protein lead to Charcot-Marie-Tooth disease type 2A pathophysiology remains unclear. We have generated a transgenic mouse expressing either a mutated (R94Q) or wild-type form of human mitofusin 2 in neurons to evaluate whether the R94Q mutation was sufficient for inducing a Charcot-Marie-Tooth disease type 2A phenotype. Only mice expressing mitofusin 2(R94Q) developed locomotor impairments and gait defects thus mimicking the Charcot-Marie-Tooth disease type 2A neuropathy. In these animals, the number of mitochondria per axon was significantly increased in the distal part of the sciatic nerve axons with a diameter smaller than 3.5 microm. Importantly, the analysis of R94Q transgenic animals also revealed an age-related shift in the size of myelinated axons leading to an over-representation of axons smaller than 3.5 microm. Together these data suggest a link between an increased number of mitochondria in axons and a shift in axonal size distribution in mitofusin 2(R94Q) transgenic animals that may contribute to their neurological phenotype.
Keywords AgingAnimalsArginineAxons/ultrastructureCharcot-Marie-Tooth Disease/genetics/pathology/physiopathologyDNA, Complementary/metabolismGTP Phosphohydrolases/geneticsGlutamineHumansMembrane Transport Proteins/geneticsMiceMice, TransgenicMicroscopy, ElectronMitochondria/ultrastructureMitochondrial Membrane Transport ProteinsMitochondrial Proteins/geneticsMutationNerve Fibers, Myelinated/pathologyNeurons/metabolismPeripheral Nerves/ultrastructurePhenotypeSciatic Nerve/pathology
PMID: 20418531
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CARTONI, Romain et al. Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A. In: Brain, 2010, vol. 133, n° Pt 5, p. 1460-1469. doi: 10.1093/brain/awq082 https://archive-ouverte.unige.ch/unige:18362

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Deposited on : 2012-02-09

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