Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod
Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleu...
| Published in: | Frontiers in Cellular Neuroscience |
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| Main Authors: | , , , , , , , , , |
| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.918041/full |
| _version_ | 1851887335693615104 |
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| author | Yasuyuki Kihara Yunjiao Zhu Deepa Jonnalagadda William Romanow Carter Palmer Carter Palmer Benjamin Siddoway Richard Rivera Ranjan Dutta Bruce D. Trapp Jerold Chun |
| author_facet | Yasuyuki Kihara Yunjiao Zhu Deepa Jonnalagadda William Romanow Carter Palmer Carter Palmer Benjamin Siddoway Richard Rivera Ranjan Dutta Bruce D. Trapp Jerold Chun |
| author_sort | Yasuyuki Kihara |
| collection | DOAJ |
| container_title | Frontiers in Cellular Neuroscience |
| description | Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2) – the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains. |
| format | Article |
| id | doaj-art-253d48ea8e324c959cd159fe3faa35e5 |
| institution | Directory of Open Access Journals |
| issn | 1662-5102 |
| language | English |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| spelling | doaj-art-253d48ea8e324c959cd159fe3faa35e52025-08-19T22:11:04ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-06-011610.3389/fncel.2022.918041918041Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of FingolimodYasuyuki Kihara0Yunjiao Zhu1Deepa Jonnalagadda2William Romanow3Carter Palmer4Carter Palmer5Benjamin Siddoway6Richard Rivera7Ranjan Dutta8Bruce D. Trapp9Jerold Chun10Translational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesBiomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, La Jolla, CA, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesDepartment of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesTranslational Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesMultiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2) – the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.https://www.frontiersin.org/articles/10.3389/fncel.2022.918041/fullneuroinflammationS1P1FTY720siponimodozanimodponesimod |
| spellingShingle | Yasuyuki Kihara Yunjiao Zhu Deepa Jonnalagadda William Romanow Carter Palmer Carter Palmer Benjamin Siddoway Richard Rivera Ranjan Dutta Bruce D. Trapp Jerold Chun Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod neuroinflammation S1P1 FTY720 siponimod ozanimod ponesimod |
| title | Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod |
| title_full | Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod |
| title_fullStr | Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod |
| title_full_unstemmed | Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod |
| title_short | Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod |
| title_sort | single nucleus rna seq of normal appearing brain regions in relapsing remitting vs secondary progressive multiple sclerosis implications for the efficacy of fingolimod |
| topic | neuroinflammation S1P1 FTY720 siponimod ozanimod ponesimod |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.918041/full |
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