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

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.

• Authors: Romain Cartoni, Estelle Arnaud, Jean-Jacques Médard, Olivier Poirot, Delphine S Courvoisier, Roman Chrast, Jean-Claude Martinou
• Journal: Brain : a journal of neurology (Brain) Vol. 133 Issue Pt 5 Pg. 1460-9 (May 2010) ISSN: 1460-2156 [Electronic] England
• PMID: 20418531 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Complementary
• Membrane Transport Proteins
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Proteins
• Glutamine
• Arginine
• GTP Phosphohydrolases
• Mfn1 protein, human

Topics

• Aging
• Animals
• Arginine
• Axons (ultrastructure)
• Charcot-Marie-Tooth Disease (genetics, pathology, physiopathology)
• 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)