Article: article from journal or magazin.
Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Aging, Animals, Arginine, Axons/ultrastructure, Charcot-Marie-Tooth Disease/genetics, Charcot-Marie-Tooth Disease/pathology, DNA, Complementary/metabolism, GTP Phosphohydrolases/genetics, Glutamine, Humans, Membrane Transport Proteins/genetics, Mice, Mice, Transgenic, Microscopy, Electron, Mitochondria/ultrastructure, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins/genetics, Mutation, Nerve Fibers, Myelinated/pathology, Neurons/metabolism, Peripheral Nerves/ultrastructure, Phenotype, Sciatic Nerve/pathology
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