Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis
Kicheol Kim1, Anne-Katrin Pröbstel1,2, Ryan Baumann1
1Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Brain : a Journal of Neurology
|December 29, 2020
Summary
Multiple sclerosis involves altered gene expression in immune cells. Targeting the NAE1 gene and neddylation pathway with pevonedistat shows promise in reducing disease severity in mouse models.
Area of Science:
- Neuroimmunology
- Genetics
- Molecular Biology
Background:
- Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease influenced by genetic and environmental factors.
- Genome-wide association studies have identified over 200 risk loci, many linked to immune cell-expressed genes.
- The translation of genetic variations into cell-specific gene expression profiles in MS remains unclear.
Purpose of the Study:
- To investigate cell type-specific gene expression alterations in treatment-naive patients with multiple sclerosis.
- To identify key genes and pathways involved in MS pathogenesis.
- To explore potential therapeutic targets for MS.
Main Methods:
- Whole transcriptome sequencing of fluorescence-activated cell sorted T cells (CD4+ and CD8+) and CD14+ monocytes.
- Comparison of gene expression profiles between 106 treatment-naive MS patients and 22 healthy controls.
- Inhibition of NEDD8 activating enzyme using pevonedistat (MLN4924) in a murine experimental autoimmune encephalomyelitis (EAE) model.
Main Results:
- Identification of 479 differentially expressed genes in CD4+ T cells, 435 in monocytes, and 54 in CD8+ T cells.
- Discovery of upregulated NAE1 gene transcripts in CD4+ T cells, a key component of the neddylation pathway.
- Significant amelioration of disease severity in the murine EAE model upon inhibition of NEDD8 activating enzyme.
Conclusions:
- Cell-specific gene expression profiles are altered in multiple sclerosis patients.
- The neddylation pathway, regulated by NAE1, plays a crucial role in MS pathogenesis.
- NEDD8 activating enzyme inhibition presents a potential therapeutic strategy for multiple sclerosis.
