MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model
Summary: Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss,...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223003474 |
| _version_ | 1811154753631027200 |
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| author | Saba Shahin Bin Lu Yueqin Zhou Hui Xu Jason Chetsawang Robert H. Baloh Shaomei Wang |
| author_facet | Saba Shahin Bin Lu Yueqin Zhou Hui Xu Jason Chetsawang Robert H. Baloh Shaomei Wang |
| author_sort | Saba Shahin |
| collection | DOAJ |
| description | Summary: Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss, color-vision defects, and progressive loss of visual acuity. We used a well-established transgenic mouse model of CMT2A with R94Q mutation on MFN2 gene (MFN2R94Q) to investigate the functional and morphological changes in retina. We documented extensive vision loss due to photoreceptor degeneration, retinal ganglion cell and their axonal loss, retinal secondary neuronal and synaptic alternation, and Müller cell gliosis in the retina of MFN2R94Q mice. Imbalanced MFN1/MFN2 ratio and dysregulated mitochondrial fusion/fission result in retinal degeneration via P62/LC3B-mediated mitophagy/autophagy in MFN2R94Q mice. Finally, transgenic MFN1 augmentation (MFN2R94Q:MFN1) rescued vision and retinal morphology to wild-type level via restoring homeostasis in mitochondrial MFN1/MFN2 ratio, fusion/fission cycle, and PINK1-dependent, Parkin-independent mitophagy. |
| first_indexed | 2024-04-10T04:21:17Z |
| format | Article |
| id | doaj.art-f9fd4a32540542fba5be4e07313e384f |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-10T04:21:17Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-f9fd4a32540542fba5be4e07313e384f2023-03-11T04:20:17ZengElsevieriScience2589-00422023-03-01263106270MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse modelSaba Shahin0Bin Lu1Yueqin Zhou2Hui Xu3Jason Chetsawang4Robert H. Baloh5Shaomei Wang6Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USABoard of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USABoard of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USABoard of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USABoard of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USABoard of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USABoard of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Corresponding authorSummary: Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss, color-vision defects, and progressive loss of visual acuity. We used a well-established transgenic mouse model of CMT2A with R94Q mutation on MFN2 gene (MFN2R94Q) to investigate the functional and morphological changes in retina. We documented extensive vision loss due to photoreceptor degeneration, retinal ganglion cell and their axonal loss, retinal secondary neuronal and synaptic alternation, and Müller cell gliosis in the retina of MFN2R94Q mice. Imbalanced MFN1/MFN2 ratio and dysregulated mitochondrial fusion/fission result in retinal degeneration via P62/LC3B-mediated mitophagy/autophagy in MFN2R94Q mice. Finally, transgenic MFN1 augmentation (MFN2R94Q:MFN1) rescued vision and retinal morphology to wild-type level via restoring homeostasis in mitochondrial MFN1/MFN2 ratio, fusion/fission cycle, and PINK1-dependent, Parkin-independent mitophagy.http://www.sciencedirect.com/science/article/pii/S2589004223003474Biological sciencesNeuroscienceMolecular neuroscienceSensory neuroscience |
| spellingShingle | Saba Shahin Bin Lu Yueqin Zhou Hui Xu Jason Chetsawang Robert H. Baloh Shaomei Wang MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model iScience Biological sciences Neuroscience Molecular neuroscience Sensory neuroscience |
| title | MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model |
| title_full | MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model |
| title_fullStr | MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model |
| title_full_unstemmed | MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model |
| title_short | MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model |
| title_sort | mfn1 augmentation prevents retinal degeneration in a charcot marie tooth type 2a mouse model |
| topic | Biological sciences Neuroscience Molecular neuroscience Sensory neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223003474 |
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