Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex
Abstract 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 fissi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | http://link.springer.com/article/10.1186/s13024-018-0238-8 |
| _version_ | 1828842695692386304 |
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| author | Sirui Jiang Priya Nandy Wenzhang Wang Xiaopin Ma Jeffrey Hsia Chunyu Wang Zhenlian Wang Mengyue Niu Sandra L. Siedlak Sandy Torres Hisashi Fujioka Ying Xu Hyoung-gon Lee George Perry Jun Liu Xiongwei Zhu |
| author_facet | Sirui Jiang Priya Nandy Wenzhang Wang Xiaopin Ma Jeffrey Hsia Chunyu Wang Zhenlian Wang Mengyue Niu Sandra L. Siedlak Sandy Torres Hisashi Fujioka Ying Xu Hyoung-gon Lee George Perry Jun Liu Xiongwei Zhu |
| author_sort | Sirui Jiang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T20:29:45Z |
| format | Article |
| id | doaj.art-42a6a82020eb417a90ffe2f2afa31f4e |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-12T20:29:45Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-42a6a82020eb417a90ffe2f2afa31f4e2022-12-22T00:13:02ZengBMCMolecular Neurodegeneration1750-13262018-02-0113111510.1186/s13024-018-0238-8Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortexSirui Jiang0Priya Nandy1Wenzhang Wang2Xiaopin Ma3Jeffrey Hsia4Chunyu Wang5Zhenlian Wang6Mengyue Niu7Sandra L. Siedlak8Sandy Torres9Hisashi Fujioka10Ying Xu11Hyoung-gon Lee12George Perry13Jun Liu14Xiongwei Zhu15Department of Pathology, Case Western Reserve UniversityDepartment of Pathology, Case Western Reserve UniversityDepartment of Pathology, Case Western Reserve UniversityDepartment of Pathology, Case Western Reserve UniversityDepartment of Pathology, Case Western Reserve UniversityDepartment of Neurology, the second Xiangya Hospital, Central South UniversitySchool of Pharmaceutical Engineering & Life Sciences, Changzhou UniversityDepartment of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pathology, Case Western Reserve UniversityDepartment of Pathology, Case Western Reserve UniversityElectron Microscopy Core Facility, Case Western Reserve UniversityDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at BuffaloDepartment of Biology, The University of Texas at San AntonioDepartment of Biology, The University of Texas at San AntonioDepartment of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pathology, Case Western Reserve UniversityAbstract 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.http://link.springer.com/article/10.1186/s13024-018-0238-8 |
| spellingShingle | Sirui Jiang Priya Nandy Wenzhang Wang Xiaopin Ma Jeffrey Hsia Chunyu Wang Zhenlian Wang Mengyue Niu Sandra L. Siedlak Sandy Torres Hisashi Fujioka Ying Xu Hyoung-gon Lee George Perry Jun Liu Xiongwei Zhu Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex Molecular Neurodegeneration |
| 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 |
| url | http://link.springer.com/article/10.1186/s13024-018-0238-8 |
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