Characterisation of Transcriptional Changes in the Spinal Cord of the Progressive Experimental Autoimmune Encephalomyelitis Biozzi ABH Mouse Model by RNA Sequencing.

Ioanna Sevastou,David L Selwood,Gareth Pryce,David Baker,David R Booth

doi:10.1371/journal.pone.0157754

Ioanna Sevastou, David L Selwood + Show 3 more

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https://doi.org/10.1371/journal.pone.0157754

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Abstract

Multiple sclerosis (MS) is a debilitating immune-mediated neurological disorder affecting young adults. MS is primarily relapsing-remitting, but neurodegeneration and disability accumulate from disease onset. The most commonly used mouse MS models exhibit a monophasic immune response with fast accumulation of neurological damage that does not allow the study of progressive neurodegeneration. The chronic relapsing and secondary progressive EAE (pEAE) Biozzi ABH mouse model of MS exhibits a reproducible relapsing-remitting disease course that slowly accumulates permanent neurological deficit and develops a post-relapsing progressive disease that permits the study of demyelination and neurodegeneration. RNA sequencing (RNAseq) was used to explore global gene expression in the pEAE Biozzi ABH mouse. Spinal cord tissue RNA from pEAE Biozzi ABH mice and healthy age-matched controls was sequenced. 2,072 genes were differentially expressed (q<0.05) from which 1,397 were significantly upregulated and 675 were significantly downregulated. This hypothesis-free investigation characterised the genomic changes that describe the pEAE mouse model. The differentially expressed genes revealed a persistent immunoreactant phenotype, combined with downregulation of the cholesterol biosynthesis superpathway and the LXR/RXR activation pathway. Genes differentially expressed include the myelination genes Slc17a7, Ugt8A and Opalin, the neuroprotective genes Sprr1A, Osm and Wisp2, as well as genes identified as MS risk factors, including RGs14 and Scap2. Novel genes with unestablished roles in EAE or MS were also identified. The identification of differentially expressed novel genes and genes involved in MS pathology, opens the door to their functional study in the pEAE mouse model which recapitulates some of the important clinical features of progressive MS.

Highlights

Multiple sclerosis (MS) is a central nervous system disease that primarily affects young adults
The spinal cord tissue RNA sequencing resulted in approximately 18–25 million reads per sample, which were aligned on the Mus musculus mm10 reference genome
Downstream statistical analysis of gene expression between control and progressive EAE (pEAE) samples (Cuffdiff) resulted in 14,373 genes successfully tested for differential expression

Summary

Introduction

Multiple sclerosis (MS) is a central nervous system disease that primarily affects young adults. MS has a median survival expectancy of 40 years after diagnosis [1], while patients start accumulating significant levels of disability early in disease progression, which adds a substantial burden to their everyday lives. The clinical presentation of MS is most commonly relapsing-remitting, but can be primary progressive, where neurodegeneration and disability accumulate from disease onset. Over time relapsing remitting MS acquires a secondary progressive phenotype, with pathology accumulating between relapses [3]. Neurological symptoms in MS reflect focal inflammatory demyelinating lesions in the central nervous system that affect saltatory conduction in the affected sites [2]. Accumulating neurological disability is accompanied by disabling symptoms such as spasticity, tremor and muscle stiffness [4]

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