Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common hereditary axonal neuropathy caused by mutations in <i>MFN2</i> encoding Mitofusin-2, a multifunctional protein located in the outer mitochondrial membrane. In order to study the effects of a novel <i>MFN2<sup>K35...
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| Autores principales: | , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/7a19fa7087544b0ab83ac09a7ccee5ab |
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| Sumario: | Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common hereditary axonal neuropathy caused by mutations in <i>MFN2</i> encoding Mitofusin-2, a multifunctional protein located in the outer mitochondrial membrane. In order to study the effects of a novel <i>MFN2<sup>K357T</sup></i> mutation associated with early onset, autosomal dominant severe CMT2A, we generated a knock-in mouse model. While <i>Mfn2<sup>K357T/K357T</sup></i> mouse pups were postnatally lethal, <i>Mfn2<sup>+/K357T</sup></i> heterozygous mice were asymptomatic and had no histopathological changes in their sciatic nerves up to 10 months of age. However, immunofluorescence analysis of <i>Mfn2<sup>+/K357T</sup></i> mice revealed aberrant mitochondrial clustering in the sciatic nerves from 6 months of age, in optic nerves from 8 months, and in lumbar spinal cord white matter at 10 months, along with microglia activation. Ultrastructural analyses confirmed dysmorphic mitochondrial aggregates in sciatic and optic nerves. After exposure of 6-month-old mice to lipopolysaccharide, <i>Mfn2<sup>+/K357T</sup></i> mice displayed a higher immune response, a more severe motor impairment, and increased CNS inflammation, microglia activation, and macrophage infiltrates. Overall, ubiquitous <i>Mfn2<sup>K357T</sup></i> expression renders the CNS and peripheral nerves of <i>Mfn2<sup>+/K357T</sup></i> mice more susceptible to mitochondrial clustering, and augments their response to inflammation, modeling some cellular mechanisms that may be relevant for the development of neuropathy in patients with CMT2A. |
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