Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis
Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expre...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/64564 |
| _version_ | 1818028363977064448 |
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| author | Tarik Seref Onur Andrew Laitman He Zhao Ryan Keyho Hyemin Kim Jennifer Wang Megan Mair Huilan Wang Lifang Li Alma Perez Maria de Haro Ying-Wooi Wan Genevera Allen Boxun Lu Ismael Al-Ramahi Zhandong Liu Juan Botas |
| author_facet | Tarik Seref Onur Andrew Laitman He Zhao Ryan Keyho Hyemin Kim Jennifer Wang Megan Mair Huilan Wang Lifang Li Alma Perez Maria de Haro Ying-Wooi Wan Genevera Allen Boxun Lu Ismael Al-Ramahi Zhandong Liu Juan Botas |
| author_sort | Tarik Seref Onur |
| collection | DOAJ |
| description | Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD. |
| first_indexed | 2024-12-10T05:02:37Z |
| format | Article |
| id | doaj.art-0f245c6836524f499bbfa918e0eb5204 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:02:37Z |
| publishDate | 2021-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0f245c6836524f499bbfa918e0eb52042022-12-22T02:01:20ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.64564Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesisTarik Seref Onur0https://orcid.org/0000-0002-3234-6263Andrew Laitman1He Zhao2Ryan Keyho3Hyemin Kim4Jennifer Wang5Megan Mair6Huilan Wang7Lifang Li8Alma Perez9Maria de Haro10Ying-Wooi Wan11Genevera Allen12Boxun Lu13Ismael Al-Ramahi14Zhandong Liu15Juan Botas16https://orcid.org/0000-0001-5476-5955Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United StatesState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, ChinaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Departments of Electrical & Computer Engineering, Statistics and Computer Science, Rice University, Houston, United StatesState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, ChinaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United StatesJan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United States; Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United StatesMost research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD.https://elifesciences.org/articles/64564Huntington's diseaseneurodegenerationgliasynaptic biologyexcitotoxicityhigh-throughput experimentation |
| spellingShingle | Tarik Seref Onur Andrew Laitman He Zhao Ryan Keyho Hyemin Kim Jennifer Wang Megan Mair Huilan Wang Lifang Li Alma Perez Maria de Haro Ying-Wooi Wan Genevera Allen Boxun Lu Ismael Al-Ramahi Zhandong Liu Juan Botas Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis eLife Huntington's disease neurodegeneration glia synaptic biology excitotoxicity high-throughput experimentation |
| title | Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis |
| title_full | Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis |
| title_fullStr | Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis |
| title_full_unstemmed | Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis |
| title_short | Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis |
| title_sort | downregulation of glial genes involved in synaptic function mitigates huntington s disease pathogenesis |
| topic | Huntington's disease neurodegeneration glia synaptic biology excitotoxicity high-throughput experimentation |
| url | https://elifesciences.org/articles/64564 |
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