Cargando…
Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex
BACKGROUND: Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and f...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796581/ https://www.ncbi.nlm.nih.gov/pubmed/29391029 http://dx.doi.org/10.1186/s13024-018-0238-8 |
_version_ | 1783297527454367744 |
---|---|
author | Jiang, Sirui Nandy, Priya Wang, Wenzhang Ma, Xiaopin Hsia, Jeffrey Wang, Chunyu Wang, Zhenlian Niu, Mengyue Siedlak, Sandra L. Torres, Sandy Fujioka, Hisashi Xu, Ying Lee, Hyoung-gon Perry, George Liu, Jun Zhu, Xiongwei |
author_facet | Jiang, Sirui Nandy, Priya Wang, Wenzhang Ma, Xiaopin Hsia, Jeffrey Wang, Chunyu Wang, Zhenlian Niu, Mengyue Siedlak, Sandra L. Torres, Sandy Fujioka, Hisashi Xu, Ying Lee, Hyoung-gon Perry, George Liu, Jun Zhu, Xiongwei |
author_sort | Jiang, Sirui |
collection | PubMed |
description | BACKGROUND: Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease. METHODS: To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD. RESULTS: Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size. CONCLUSIONS: Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0238-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5796581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57965812018-02-12 Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex Jiang, Sirui Nandy, Priya Wang, Wenzhang Ma, Xiaopin Hsia, Jeffrey Wang, Chunyu Wang, Zhenlian Niu, Mengyue Siedlak, Sandra L. Torres, Sandy Fujioka, Hisashi Xu, Ying Lee, Hyoung-gon Perry, George Liu, Jun Zhu, Xiongwei Mol Neurodegener Research Article BACKGROUND: Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease. METHODS: To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD. RESULTS: Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size. CONCLUSIONS: Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0238-8) contains supplementary material, which is available to authorized users. BioMed Central 2018-02-01 /pmc/articles/PMC5796581/ /pubmed/29391029 http://dx.doi.org/10.1186/s13024-018-0238-8 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Jiang, Sirui Nandy, Priya Wang, Wenzhang Ma, Xiaopin Hsia, Jeffrey Wang, Chunyu Wang, Zhenlian Niu, Mengyue Siedlak, Sandra L. Torres, Sandy Fujioka, Hisashi Xu, Ying Lee, Hyoung-gon Perry, George Liu, Jun Zhu, Xiongwei Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
title | Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
title_full | Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
title_fullStr | Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
title_full_unstemmed | Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
title_short | Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
title_sort | mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796581/ https://www.ncbi.nlm.nih.gov/pubmed/29391029 http://dx.doi.org/10.1186/s13024-018-0238-8 |
work_keys_str_mv | AT jiangsirui mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT nandypriya mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT wangwenzhang mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT maxiaopin mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT hsiajeffrey mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT wangchunyu mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT wangzhenlian mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT niumengyue mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT siedlaksandral mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT torressandy mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT fujiokahisashi mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT xuying mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT leehyounggon mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT perrygeorge mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT liujun mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex AT zhuxiongwei mfn2ablationcausesanoxidativestressresponseandeventualneuronaldeathinthehippocampusandcortex |