A missense mutation in Tbce causes progressive motor neuronopathy in mice
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Published on: November 14, 2016
Natalia Martin1, Jean Jaubert, Pierre Gounon
1Unité de Génétique des Mammifères, Institut Pasteur, 25 Rue du Docteur Roux, F-75724 Paris Cedex 15, France.
Abstract:
Mice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation (chromosome 13) develop a progressive caudio-cranial degeneration of their motor axons from the age of two weeks and die four to six weeks after birth. The mutation is fully penetrant, and expressivity does not depend on the genetic background. Based on its pathological features, the pmn mutation has been considered an excellent model for the autosomal recessive proximal childhood form of spinal muscular atrophy (SMA). Previously, we demonstrated that the genes responsible for these disorders were not orthologous. Here, we identify the pmn mutation as resulting in a Trp524Gly substitution at the last residue of the tubulin-specific chaperone e (Tbce) protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. Our observations indicate that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggest that altered function of tubulin cofactors might be implicated in human motor neuron diseases.
Insights
The progressive motor neuronopathy (pmn) mutation in mice causes motor axon degeneration due to a defect in the tubulin-specific chaperone e (Tbce) protein. Restoring Tbce function corrects the motor neuron disease phenotype.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The progressive motor neuronopathy (pmn) mutation in mice models spinal muscular atrophy (SMA).
- Previous studies ruled out orthology between pmn and SMA genes.
- The pmn mutation causes progressive motor axon degeneration and early death in mice.
Purpose of the Study:
- To identify the genetic cause of the pmn mutation.
- To investigate the role of the affected protein in motor neuron function.
- To explore the potential link between tubulin cofactor dysfunction and human motor neuron diseases.
Main Methods:
- Genetic sequencing to identify the pmn mutation.
- Protein analysis to assess stability and function.
- Electron microscopy to examine microtubule structure in motor axons.
- Transgenic complementation to validate the role of Tbce.
Main Results:
- The pmn mutation results in a Trp524Gly substitution in the tubulin-specific chaperone e (Tbce) protein.
- This substitution decreases Tbce protein stability, leading to reduced microtubule numbers in motor axons.
- Transgenic expression of wildtype Tbce rescued the motor neuron degeneration phenotype in pmn mice.
Conclusions:
- Tbce is essential for maintaining microtubule integrity in mouse motor axons.
- Defects in tubulin cofactors, like Tbce, may contribute to human motor neuron diseases.
- The pmn mouse model provides insights into the molecular mechanisms underlying motor neuron degeneration.
