1. Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
- Author
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Ji Hyun Bae, Irene Sargiannidou, Louiza Potamiti, Kleopas A. Kleopa, Mihalis I. Panayiotidis, Jae Young Lee, Filippos Stavropoulos, Su Cheong Yeom, and Alexia Kagiava
- Subjects
Male ,Charcot-Marie-Tooth disease type 2A ,Pathology ,medicine.medical_specialty ,peripheral neuropathy ,Lipopolysaccharide ,QH301-705.5 ,MFN2 ,Inflammation ,Mitochondrion ,Mitochondrial Dynamics ,Article ,Catalysis ,neuroinflammation ,Mitochondrial Proteins ,Inorganic Chemistry ,White matter ,Mice ,chemistry.chemical_compound ,Charcot-Marie-Tooth Disease ,medicine ,Animals ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,Neuroinflammation ,knock-in mouse model ,Microglia ,business.industry ,lipopolysaccharide ,Organic Chemistry ,Immunity ,General Medicine ,medicine.disease ,mitofusin-2 ,Computer Science Applications ,Mice, Inbred C57BL ,mitochondria ,Chemistry ,Disease Models, Animal ,medicine.anatomical_structure ,Peripheral neuropathy ,chemistry ,Neuroinflammatory Diseases ,medicine.symptom ,business - Abstract
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common hereditary axonal neuropathy caused by mutations in MFN2 encoding Mitofusin-2, a multifunctional protein located in the outer mitochondrial membrane. In order to study the effects of a novel MFN2K357T mutation associated with early onset, autosomal dominant severe CMT2A, we generated a knock-in mouse model. While Mfn2K357T/K357T mouse pups were postnatally lethal, Mfn2+/K357T heterozygous mice were asymptomatic and had no histopathological changes in their sciatic nerves up to 10 months of age. However, immunofluorescence analysis of Mfn2+/K357T 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, Mfn2+/K357T mice displayed a higher immune response, a more severe motor impairment, and increased CNS inflammation, microglia activation, and macrophage infiltrates. Overall, ubiquitous Mfn2K357T expression renders the CNS and peripheral nerves of Mfn2+/K357T 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.
- Published
- 2021
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