PUBLICATION

Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish

Authors
Chapman, A.L., Bennett, E.J., Ramesh, T.M., De Vos, K.J., and Grierson, A.J.
ID
ZDB-PUB-130712-16
Date
2013
Source
PLoS One   8(6): e67276 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Homozygote
  • Zebrafish*
  • Mutation*
  • Animals
  • GTP Phosphohydrolases
  • Disease Models, Animal
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Mitochondria/metabolism
  • Humans
  • Amino Acid Sequence
  • Neurons/metabolism
  • Motor Activity/genetics
  • Charcot-Marie-Tooth Disease/genetics*
  • Charcot-Marie-Tooth Disease/metabolism*
  • Charcot-Marie-Tooth Disease/pathology
  • Charcot-Marie-Tooth Disease/physiopathology
  • Axonal Transport/genetics*
(all 19)
PubMed
23840650 Full text @ PLoS One
Abstract

Charcot-Marie-Tooth disease (CMT) represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1) or distal axon degeneration (CMT2) of motor and sensory neurons. The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2); an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. The mechanism of action of MFN2 mutations is still not fully resolved. To investigate a role for loss of Mfn2 function in disease we investigated an ENU-induced nonsense mutation in zebrafish MFN2 and characterised the phenotype of these fish at the whole organism, pathological, and subcellular level. We show that unlike mice, loss of MFN2 function in zebrafish leads to an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to CMT2. Mutant zebrafish show progressive loss of swimming associated with alterations at the neuro-muscular junction. At the cellular level, we provide direct evidence that mitochondrial transport along axons is perturbed in Mfn2 mutant zebrafish, suggesting that this is a key mechanism of disease in CMT. The progressive phenotype and pathology suggest that zebrafish will be useful for further investigating the disease mechanism and potential treatment of axonal forms of CMT. Our findings support the idea that MFN2 mutation status should be investigated in patients presenting with early-onset recessively inherited axonal CMT.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu3528
    Point Mutation
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    No data available
    Fish
    1 - 2 of 2
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    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available