Proximity Extension Assay identifies new targets of grey matter pathology in multiple sclerosis

Grey matter (GM) lesions and atrophy in multiple sclerosis (MS) are strongly correlated to disease progression and cognitive decline, but molecular mechanisms underlying GM lesion formation remain unclear. Various studies have used a proteomics approach to study changes in cerebrospinal fluid or blood. However, very few studies have been performed in tissue and especially GM lesions are understudied, despite the importance of these lesions in disease progression. For this explorative study, we applied Olink proteomics to unravel differentially expressed proteins in the GM of MS patients (n = 9) compared to controls (n = 10). First, we evaluated which of the 184 proteins in a neurology and inflammation panel could accurately distinguish MS from control by applying a classifier based on unbiased variable selection. The classifier consisted of five proteins: HGF, PVR, NEP, EFNA4 and LAP.TGF.beta1. These were all differentially expressed in GMLs of MS patients (FDR < 0.1), amongst twelve others. Additionally, we studied proteomic changes between MS cases with different GM lesion loads and identified IL-20, CD5 and GZMA to distinguish large from small lesions. Eight other proteins were nominally differentially expressed based on lesion load. Future studies should explore the potential of targeting these proteins to hamper grey matter pathology.