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Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegenerati...

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Autores principales: Han, Song, Nandy, Priya, Austria, Quillan, Siedlak, Sandra L., Torres, Sandy, Fujioka, Hisashi, Wang, Wenzhang, Zhu, Xiongwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017224/
https://www.ncbi.nlm.nih.gov/pubmed/31947766
http://dx.doi.org/10.3390/cells9010116
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author Han, Song
Nandy, Priya
Austria, Quillan
Siedlak, Sandra L.
Torres, Sandy
Fujioka, Hisashi
Wang, Wenzhang
Zhu, Xiongwei
author_facet Han, Song
Nandy, Priya
Austria, Quillan
Siedlak, Sandra L.
Torres, Sandy
Fujioka, Hisashi
Wang, Wenzhang
Zhu, Xiongwei
author_sort Han, Song
collection PubMed
description It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways.
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spelling pubmed-70172242020-02-28 Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death Han, Song Nandy, Priya Austria, Quillan Siedlak, Sandra L. Torres, Sandy Fujioka, Hisashi Wang, Wenzhang Zhu, Xiongwei Cells Article It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways. MDPI 2020-01-03 /pmc/articles/PMC7017224/ /pubmed/31947766 http://dx.doi.org/10.3390/cells9010116 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Han, Song
Nandy, Priya
Austria, Quillan
Siedlak, Sandra L.
Torres, Sandy
Fujioka, Hisashi
Wang, Wenzhang
Zhu, Xiongwei
Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
title Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
title_full Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
title_fullStr Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
title_full_unstemmed Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
title_short Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
title_sort mfn2 ablation in the adult mouse hippocampus and cortex causes neuronal death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017224/
https://www.ncbi.nlm.nih.gov/pubmed/31947766
http://dx.doi.org/10.3390/cells9010116
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