Gene expression profiling of grey matter lesions in secondary progressive multiple sclerosis

Background: Multiple sclerosis (MS) is an inflammatory demyeli-nating disease with widespread cortical lesions as one of the pathological hallmarks. However, our understanding of pathogenetic mechanisms involved in grey matter lesion formation is limited. Objective: Here, we aim to provide a transcriptome analysis of cortical grey matter lesions, hence advancing our understanding of lesion pathogenesis and identifying potential novel biomarkers and therapeutic targets. Methods: Grey matter lesions (type 3 - subpial lesions) were identified in the superior frontal gyrus (SFG) from 10 patients with secondary progressive MS and age-matched with SFG grey matter from controls with no neurological disorders. Gene expression analysis was performed on RNA extracted from grey matter lesions dissected from snap frozen tissues with the Illumina whole genome HumanRef8 v2 BeadChip. Results: A total of 2,058 genes were differentially expressed (p < 0.01) with a greater than a 1.4-fold change in 688 genes. Levels of mRNA from selected genes were confirmed using quantitative real-time polymerase chain reaction. The most highly expressed gene transcripts found in grey matter lesions were in response to oxidative stress (metallothioneins and S100A10), cellular stress (heat shock proteins), inflammation (ALOX5AP), cell motility (CYP2J2, osteopontin/CD44, palladin), blood-brain-barrier disruption (PECAM1 and tissue inhibitor of metalloproteinase 1), cell cycle control (BCL-6, PML and RUNX3) and interferon (IFTTM1, 2 & 3). Most under expressed genes were associated with myelin loss (MOBP), neuronal loss (parvalbumin and VGF nerve growth factor inducible) and lipid/cholesterol metabolism (coenzyme A reductase). Conclusions: Cell cycle control was the most overrepresented functional category placing an emphasis on apoptosis and attempts at apoptotic rescue. A detailed assessment of the cell populations in which this is occurring may prove useful in advancing our knowledge in lesion pathology.