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:	Filippos Stavropoulos, Irene Sargiannidou, Louiza Potamiti, Alexia Kagiava, Mihalis I. Panayiotidis, Ji Hyun Bae, Su Cheong Yeom, Jae Young Lee, Kleopas A. Kleopa
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Charcot-Marie-Tooth disease type 2A peripheral neuropathy knock-in mouse model mitofusin-2 mitochondria lipopolysaccharide Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/7a19fa7087544b0ab83ac09a7ccee5ab
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spelling	oai:doaj.org-article:7a19fa7087544b0ab83ac09a7ccee5ab2021-11-11T17:03:11ZAberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A10.3390/ijms2221115691422-00671661-6596https://doaj.org/article/7a19fa7087544b0ab83ac09a7ccee5ab2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11569https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Charcot-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.Filippos StavropoulosIrene SargiannidouLouiza PotamitiAlexia KagiavaMihalis I. PanayiotidisJi Hyun BaeSu Cheong YeomJae Young LeeKleopas A. KleopaMDPI AGarticleCharcot-Marie-Tooth disease type 2Aperipheral neuropathyknock-in mouse modelmitofusin-2mitochondrialipopolysaccharideBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11569, p 11569 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Charcot-Marie-Tooth disease type 2A peripheral neuropathy knock-in mouse model mitofusin-2 mitochondria lipopolysaccharide Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Charcot-Marie-Tooth disease type 2A peripheral neuropathy knock-in mouse model mitofusin-2 mitochondria lipopolysaccharide Biology (General) QH301-705.5 Chemistry QD1-999 Filippos Stavropoulos Irene Sargiannidou Louiza Potamiti Alexia Kagiava Mihalis I. Panayiotidis Ji Hyun Bae Su Cheong Yeom Jae Young Lee Kleopas A. Kleopa Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
description	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.
format	article
author	Filippos Stavropoulos Irene Sargiannidou Louiza Potamiti Alexia Kagiava Mihalis I. Panayiotidis Ji Hyun Bae Su Cheong Yeom Jae Young Lee Kleopas A. Kleopa
author_facet	Filippos Stavropoulos Irene Sargiannidou Louiza Potamiti Alexia Kagiava Mihalis I. Panayiotidis Ji Hyun Bae Su Cheong Yeom Jae Young Lee Kleopas A. Kleopa
author_sort	Filippos Stavropoulos
title	Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
title_short	Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
title_full	Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
title_fullStr	Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
title_full_unstemmed	Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A
title_sort	aberrant mitochondrial dynamics and exacerbated response to neuroinflammation in a novel mouse model of cmt2a
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7a19fa7087544b0ab83ac09a7ccee5ab
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Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A

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