Journal
BRAIN
Volume 133, Issue -, Pages 1460-1469Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awq082
Keywords
Charcot-Marie-Tooth type 2A; mitofusin 2; mitochondrial fusion; mouse model; transgenic mouse
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Funding
- Swiss National Science Foundation [31003A_124968/1, PP00P3_124833/1]
- Association Francaise contre les Myopathies [F12214A/501816]
- Fondation TELETHON action Suisse
- Swiss National Science Foundation (SNF) [31003A_124968, PP00P3_124833] Funding Source: Swiss National Science Foundation (SNF)
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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 mu m. 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 mu m. 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.
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