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...
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| Published in | eLife Vol. 10 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
eLife Science Publications, Ltd
19.04.2021
eLife Sciences Publications Ltd eLife Sciences Publications, Ltd |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2050-084X 2050-084X |
| DOI | 10.7554/eLife.64564 |
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| Abstract | 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
(m
HTT
) 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 d
NRXN3
function in glia was sufficient to improve the phenotype of flies expressing m
HTT
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.
When a neuron dies, through injury or disease, the body loses all communication that passes through it. The brain compensates by rerouting the flow of information through other neurons in the network. Eventually, if the loss of neurons becomes too great, compensation becomes impossible. This process happens in Alzheimer's, Parkinson's, and Huntington's disease. In the case of Huntington's disease, the cause is mutation to a single gene known as huntingtin. The mutation is present in every cell in the body but causes particular damage to parts of the brain involved in mood, thinking and movement.
Neurons and other cells respond to mutations in the huntingtin gene by turning the activities of other genes up or down, but it is not clear whether all of these changes contribute to the damage seen in Huntington's disease. In fact, it is possible that some of the changes are a result of the brain trying to protect itself. So far, most research on this subject has focused on neurons because the huntingtin gene plays a role in maintaining healthy neuronal connections. But, given that all cells carry the mutated gene, it is likely that other cells are also involved. The glia are a diverse group of cells that support the brain, providing care and sustenance to neurons. These cells have a known role in maintaining the connections between neurons and may also have play a role in either causing or correcting the damage seen in Huntington's disease.
The aim of Onur et al. was to find out which genes are affected by having a mutant huntingtin gene in neurons or glia, and whether severity of Huntington’s disease improved or worsened when the activity of these genes changed. First, Onur et al. identified genes affected by mutant huntingtin by comparing healthy human brains to the brains of people with Huntington's disease. Repeating the same comparison in mice and fruit flies identified genes affected in the same way across all three species, revealing that, in Huntington's disease, the brain dials down glial cell genes involved in maintaining neuronal connections.
To find out how these changes in gene activity affect disease severity and progression, Onur et al. manipulated the activity of each of the genes they had identified in fruit flies that carried mutant versions of huntingtin either in neurons, in glial cells or in both cell types. They then filmed the flies to see the effects of the manipulation on movement behaviors, which are affected by Huntington’s disease. This revealed that purposely lowering the activity of the glial genes involved in maintaining connections between neurons improved the symptoms of the disease, but only in flies who had mutant huntingtin in their glial cells. This indicates that the drop in activity of these genes observed in Huntington’s disease is the brain trying to protect itself.
This work suggests that it is important to include glial cells in studies of neurological disorders. It also highlights the fact that changes in gene expression as a result of a disease are not always bad. Many alterations are compensatory, and try to either make up for or protect cells affected by the disease. Therefore, it may be important to consider whether drugs designed to treat a condition by changing levels of gene activity might undo some of the body's natural protection. Working out which changes drive disease and which changes are protective will be essential for designing effective treatments. |
|---|---|
| AbstractList | 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. 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. eLife digest When a neuron dies, through injury or disease, the body loses all communication that passes through it. The brain compensates by rerouting the flow of information through other neurons in the network. Eventually, if the loss of neurons becomes too great, compensation becomes impossible. This process happens in Alzheimer's, Parkinson's, and Huntington's disease. In the case of Huntington's disease, the cause is mutation to a single gene known as huntingtin. The mutation is present in every cell in the body but causes particular damage to parts of the brain involved in mood, thinking and movement. Neurons and other cells respond to mutations in the huntingtin gene by turning the activities of other genes up or down, but it is not clear whether all of these changes contribute to the damage seen in Huntington's disease. In fact, it is possible that some of the changes are a result of the brain trying to protect itself. So far, most research on this subject has focused on neurons because the huntingtin gene plays a role in maintaining healthy neuronal connections. But, given that all cells carry the mutated gene, it is likely that other cells are also involved. The glia are a diverse group of cells that support the brain, providing care and sustenance to neurons. These cells have a known role in maintaining the connections between neurons and may also have play a role in either causing or correcting the damage seen in Huntington's disease. The aim of Onur et al. was to find out which genes are affected by having a mutant huntingtin gene in neurons or glia, and whether severity of Huntington's disease improved or worsened when the activity of these genes changed. First, Onur et al. identified genes affected by mutant huntingtin by comparing healthy human brains to the brains of people with Huntington's disease. Repeating the same comparison in mice and fruit flies identified genes affected in the same way across all three species, revealing that, in Huntington's disease, the brain dials down glial cell genes involved in maintaining neuronal connections. To find out how these changes in gene activity affect disease severity and progression, Onur et al. manipulated the activity of each of the genes they had identified in fruit flies that carried mutant versions of huntingtin either in neurons, in glial cells or in both cell types. They then filmed the flies to see the effects of the manipulation on movement behaviors, which are affected by Huntington's disease. This revealed that purposely lowering the activity of the glial genes involved in maintaining connections between neurons improved the symptoms of the disease, but only in flies who had mutant huntingtin in their glial cells. This indicates that the drop in activity of these genes observed in Huntington's disease is the brain trying to protect itself. This work suggests that it is important to include glial cells in studies of neurological disorders. It also highlights the fact that changes in gene expression as a result of a disease are not always bad. Many alterations are compensatory, and try to either make up for or protect cells affected by the disease. Therefore, it may be important to consider whether drugs designed to treat a condition by changing levels of gene activity might undo some of the body's natural protection. Working out which changes drive disease and which changes are protective will be essential for designing effective treatments. 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 (m HTT ) 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 d NRXN3 function in glia was sufficient to improve the phenotype of flies expressing m HTT 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. When a neuron dies, through injury or disease, the body loses all communication that passes through it. The brain compensates by rerouting the flow of information through other neurons in the network. Eventually, if the loss of neurons becomes too great, compensation becomes impossible. This process happens in Alzheimer's, Parkinson's, and Huntington's disease. In the case of Huntington's disease, the cause is mutation to a single gene known as huntingtin. The mutation is present in every cell in the body but causes particular damage to parts of the brain involved in mood, thinking and movement. Neurons and other cells respond to mutations in the huntingtin gene by turning the activities of other genes up or down, but it is not clear whether all of these changes contribute to the damage seen in Huntington's disease. In fact, it is possible that some of the changes are a result of the brain trying to protect itself. So far, most research on this subject has focused on neurons because the huntingtin gene plays a role in maintaining healthy neuronal connections. But, given that all cells carry the mutated gene, it is likely that other cells are also involved. The glia are a diverse group of cells that support the brain, providing care and sustenance to neurons. These cells have a known role in maintaining the connections between neurons and may also have play a role in either causing or correcting the damage seen in Huntington's disease. The aim of Onur et al. was to find out which genes are affected by having a mutant huntingtin gene in neurons or glia, and whether severity of Huntington’s disease improved or worsened when the activity of these genes changed. First, Onur et al. identified genes affected by mutant huntingtin by comparing healthy human brains to the brains of people with Huntington's disease. Repeating the same comparison in mice and fruit flies identified genes affected in the same way across all three species, revealing that, in Huntington's disease, the brain dials down glial cell genes involved in maintaining neuronal connections. To find out how these changes in gene activity affect disease severity and progression, Onur et al. manipulated the activity of each of the genes they had identified in fruit flies that carried mutant versions of huntingtin either in neurons, in glial cells or in both cell types. They then filmed the flies to see the effects of the manipulation on movement behaviors, which are affected by Huntington’s disease. This revealed that purposely lowering the activity of the glial genes involved in maintaining connections between neurons improved the symptoms of the disease, but only in flies who had mutant huntingtin in their glial cells. This indicates that the drop in activity of these genes observed in Huntington’s disease is the brain trying to protect itself. This work suggests that it is important to include glial cells in studies of neurological disorders. It also highlights the fact that changes in gene expression as a result of a disease are not always bad. Many alterations are compensatory, and try to either make up for or protect cells affected by the disease. Therefore, it may be important to consider whether drugs designed to treat a condition by changing levels of gene activity might undo some of the body's natural protection. Working out which changes drive disease and which changes are protective will be essential for designing effective treatments. 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 expressing human mutant (m ) 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 d function in glia was sufficient to improve the phenotype of flies expressing m 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. 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.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. |
| Audience | Academic |
| Author | Li, Lifang Liu, Zhandong Zhao, He Mair, Megan Allen, Genevera Wang, Huilan Al-Ramahi, Ismael de Haro, Maria Wan, Ying-Wooi Botas, Juan Onur, Tarik Seref Wang, Jennifer Keyho, Ryan Kim, Hyemin Laitman, Andrew Perez, Alma Lu, Boxun |
| Author_xml | – sequence: 1 givenname: Tarik Seref orcidid: 0000-0002-3234-6263 surname: Onur fullname: Onur, Tarik Seref organization: Department 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 – sequence: 2 givenname: Andrew surname: Laitman fullname: Laitman, Andrew organization: Jan 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 States – sequence: 3 givenname: He surname: Zhao fullname: Zhao, He organization: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States – sequence: 4 givenname: Ryan surname: Keyho fullname: Keyho, Ryan organization: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States – sequence: 5 givenname: Hyemin surname: Kim fullname: Kim, Hyemin organization: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States – sequence: 6 givenname: Jennifer surname: Wang fullname: Wang, Jennifer organization: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States – sequence: 7 givenname: Megan surname: Mair fullname: Mair, Megan organization: Department 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 – sequence: 8 givenname: Huilan surname: Wang fullname: Wang, Huilan organization: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China – sequence: 9 givenname: Lifang surname: Li fullname: Li, Lifang organization: Department 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 – sequence: 10 givenname: Alma surname: Perez fullname: Perez, Alma organization: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States – sequence: 11 givenname: Maria surname: de Haro fullname: de Haro, Maria organization: Department 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 – sequence: 12 givenname: Ying-Wooi surname: Wan fullname: Wan, Ying-Wooi organization: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States – sequence: 13 givenname: Genevera surname: Allen fullname: Allen, Genevera organization: Jan 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 States – sequence: 14 givenname: Boxun surname: Lu fullname: Lu, Boxun organization: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China – sequence: 15 givenname: Ismael surname: Al-Ramahi fullname: Al-Ramahi, Ismael organization: Department 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 – sequence: 16 givenname: Zhandong surname: Liu fullname: Liu, Zhandong organization: Jan 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 States – sequence: 17 givenname: Juan orcidid: 0000-0001-5476-5955 surname: Botas fullname: Botas, Juan organization: Department 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 States |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33871358$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2021, Onur et al. COPYRIGHT 2021 eLife Science Publications, Ltd. 2021, Onur et al. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2021, Onur et al 2021 Onur et al |
| Copyright_xml | – notice: 2021, Onur et al. – notice: COPYRIGHT 2021 eLife Science Publications, Ltd. – notice: 2021, Onur et al. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2021, Onur et al 2021 Onur et al |
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| DOI | 10.7554/eLife.64564 |
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| Keywords | computational biology systems biology mouse genetics genomics D. melanogaster human |
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| SubjectTerms | Animal behavior Brain Brain damage Comparative analysis Computational and Systems Biology Development and progression Drosophila Excitotoxicity Fruit-flies Gene expression Gene mutations Genes Genetic aspects Genetic research Genetics and Genomics glia high-throughput experimentation Huntingtin Huntington's disease Huntingtons disease Information management Insects Medical research Medicine, Experimental Nervous system diseases neurodegeneration Neurodegenerative diseases Neuronal-glial interactions Neurons Pathogenesis Phenotypes Principal components analysis Proteins Synapses synaptic biology Synaptogenesis |
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| Title | Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis |
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