Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice
Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesi...
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BMC
2025-02-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-024-00792-y |
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| author | Ali Yousefian-Jazi Suhyun Kim Jiyeon Chu Seung-Hye Choi Phuong Thi Thanh Nguyen Uiyeol Park Min-gyeong Kim Hongik Hwang Kyungeun Lee Yeyun Kim Seung Jae Hyeon Hyewhon Rhim Hannah L. Ryu Grewo Lim Thor D. Stein Kayeong Lim Hoon Ryu Junghee Lee |
| author_facet | Ali Yousefian-Jazi Suhyun Kim Jiyeon Chu Seung-Hye Choi Phuong Thi Thanh Nguyen Uiyeol Park Min-gyeong Kim Hongik Hwang Kyungeun Lee Yeyun Kim Seung Jae Hyeon Hyewhon Rhim Hannah L. Ryu Grewo Lim Thor D. Stein Kayeong Lim Hoon Ryu Junghee Lee |
| author_sort | Ali Yousefian-Jazi |
| collection | DOAJ |
| description | Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Methods Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis. Results Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Conclusions Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments. |
| format | Article |
| id | doaj-art-5dcd6fb38273477e8a9538fac4c6aa10 |
| institution | Kabale University |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-5dcd6fb38273477e8a9538fac4c6aa102025-02-09T12:54:13ZengBMCMolecular Neurodegeneration1750-13262025-02-0120111810.1186/s13024-024-00792-yLoss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in miceAli Yousefian-Jazi0Suhyun Kim1Jiyeon Chu2Seung-Hye Choi3Phuong Thi Thanh Nguyen4Uiyeol Park5Min-gyeong Kim6Hongik Hwang7Kyungeun Lee8Yeyun Kim9Seung Jae Hyeon10Hyewhon Rhim11Hannah L. Ryu12Grewo Lim13Thor D. Stein14Kayeong Lim15Hoon Ryu16Junghee Lee17Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Severance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of MedicineLaboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)KIST School, Division of Bio-Medical Science & Technology, University of Science and Technology (UST)Department of Life Science, University of SeoulAdvanced Analysis Data Center, Korea Institute of Science and Technology (KIST)Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Brain Science Institute, Korea Institute of Science and Technology (KIST)Boston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University Chobanian & Avedisian School of MedicineBoston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University Chobanian & Avedisian School of MedicineBoston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University Chobanian & Avedisian School of MedicineBrain Science Institute, Korea Institute of Science and Technology (KIST)Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST)Boston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University Chobanian & Avedisian School of MedicineAbstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Methods Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis. Results Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Conclusions Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.https://doi.org/10.1186/s13024-024-00792-yMEF2CSingle nucleotide polymorphism (SNP)MitochondriaMotor neuronEpigenetics |
| spellingShingle | Ali Yousefian-Jazi Suhyun Kim Jiyeon Chu Seung-Hye Choi Phuong Thi Thanh Nguyen Uiyeol Park Min-gyeong Kim Hongik Hwang Kyungeun Lee Yeyun Kim Seung Jae Hyeon Hyewhon Rhim Hannah L. Ryu Grewo Lim Thor D. Stein Kayeong Lim Hoon Ryu Junghee Lee Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice Molecular Neurodegeneration MEF2C Single nucleotide polymorphism (SNP) Mitochondria Motor neuron Epigenetics |
| title | Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice |
| title_full | Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice |
| title_fullStr | Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice |
| title_full_unstemmed | Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice |
| title_short | Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice |
| title_sort | loss of mef2c function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice |
| topic | MEF2C Single nucleotide polymorphism (SNP) Mitochondria Motor neuron Epigenetics |
| url | https://doi.org/10.1186/s13024-024-00792-y |
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