Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A.
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.
Cartoni
Romain
R
Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland.
Arnaud
Estelle
E
Médard
Jean-Jacques
JJ
Poirot
Olivier
O
Courvoisier
Delphine S
DS
Chrast
Roman
R
Martinou
Jean-Claude
JC
D000375:Aging; D000818:Animals; D001120:Arginine; D001369:Axons / Q000648:ultrastructure; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018076:DNA, Complementary / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005973:Glutamine; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010525:Peripheral Nerves / Q000648:ultrastructure; D010641:Phenotype; D012584:Sciatic Nerve / Q000473:pathology
D018076:DNA, Complementary; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D005973:Glutamine; D001120:Arginine; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human