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bioRxiv · 10.1101/2022.01.10.475705

Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis

Kihara, Y.·Zhu, Y.·Jonnalagadda, D.·Romanow, W.·Palmer, C.·Siddoway, B.·Rivera, R.·Dutta, R.·Trapp, B. D.·Chun, J.
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Abstract

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.

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Kihara, Y., Zhu, Y., Jonnalagadda, D., Romanow, W., Palmer, C., Siddoway, B., Rivera, R., Dutta, R., Trapp, B. D., Chun, J.. 2022-01-12. Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis. https://doi.org/10.1101/2022.01.10.475705

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