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조회735

University of California, San Francisco

Brain, Published: 29 December 2020 | https://doi.org/10.1093/brain/awaa421 Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis

Kicheol Kim,^1,† Anne-Katrin Probstel,^1,2,† Ryan Baumann,¹ Julia Dyckow,³ James Landefeld,¹ Elva Kogl,¹ Lohith Madireddy,¹ Rita Loudermilk,¹ Erica L. Eggers,¹ Sneha Singh,¹ Stacy J. Caillier,¹ Stephen L. Hauser,¹ Bruce A. C. Cree,¹ UCSF MS-EPIC Team,¹ Lucas Schirmer,³ Michael R. Wilson¹ and Sergio E. Baranzini^1,4,5

¹Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA
²Neurologic Clinic and Policlinic, Departments of Medicine and Biomedicine, University Hospital of Basel, University of Basel, Basel, Switzerland
³Department of Neurology and Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Interdisciplinary Center for Neurosciences, University of Heidelberg, Mannheim, Germany
⁴Institute for Human Genetics, University of California, San Francisco, CA, USA
⁵Graduate Program in Bioinformatics, University of California, San Francisco, CA, USA

^†These authors contributed equally to this work.

Correspondence to: Sergio E. Baranzini, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA

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.

Keywords: multiple sclerosis; transcriptomics; neddylation

논문정보

형식Research article
게재일2020년 12월 (BRIC 등록일 2021-01-06)
연구진국외 연구진
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