Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis

Abstract

Multiple sclerosis is an autoimmune disease of the CNS in which both genetic and environmental factors are involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbour genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in patients with multiple sclerosis are still open questions in the field. To assess cell type-specific gene expression in a large cohort of patients with multiple sclerosis, we sequenced the whole transcriptome of fluorescence-activated cell sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive patients with multiple sclerosis (n = 106) and healthy subjects (n = 22). We identified 479 differentially expressed genes in CD4+ T cells, 435 in monocytes, and 54 in CD8+ T cells. Importantly, in CD4+ T cells, we discovered upregulated transcripts from the NAE1 gene, a critical subunit of the NEDD8 activating enzyme, which activates the neddylation pathway, a post-translational modification analogous to ubiquitination. Finally, we demonstrated that inhibition of NEDD8 activating enzyme using the specific inhibitor pevonedistat (MLN4924) significantly ameliorated disease severity in murine experimental autoimmune encephalomyelitis. Our findings provide novel insights into multiple sclerosis-associated gene regulation unravelling neddylation as a crucial pathway in multiple sclerosis pathogenesis with implications for the development of tailored disease-modifying agents.

Comprehensive Profiling Reveals Prognostic and Immunogenic Characteristics of Necroptosis in Soft Tissue Sarcomas

“…We found protein networks and key genes through PPI network analysis. ( ) ( 29 ). Cytoscape software (version 3.8.2) was used to further analyze the network of NRGs.…”

A Spatial Transcriptomics Study of the Brain-Electrode Interface in Rat Motor Cortex

“…This approach has been especially successful for studying diseases of the central nervous system (CNS) due to the incredible complexity and heterogeneity of cell types in the brain. For example, transcriptomics has revealed a novel target, neddylation, that ameliorates the severity of multiple sclerosis in a murine disease model 19 . Transcriptomics has also been applied in Alzheimer's disease (AD) research to expose genetic, cell-type specific regulators of myelination that are perturbed in AD, as well as sex differences in the cellular response to AD 20 .…”

Prevention of MS Requires Intervention on the Causes of the Disease: Reconciling Genes, Epigenetics, and Epstein Barr Virus

“…A further example might be drawn from a study of cell-type specific transcriptomics (80), which identified genes involved in Neddylation as differentially expressed in the lymphocytes (T cells) of MS cases vs. controls. This is striking because Neddylation is evidently also a critical process for EBV and other herpes viruses, so much so that the EBV carries its own deneddylase enzyme amongst its tegument proteins, and antibodies against this viral protein (encoded by gene BPLF1) have recently been identified as a predictor of EBV viral load using an unbiased antibody screening method (80)(81)(82). Pharmacological targeting of viral enzymes is a potential therapeutic strategy, and so may be another fruitful avenue for further exploration.…”