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| Verfasst von: | Kim, Kicheol [VerfasserIn]  |
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| | Pröbstel, Anne-Katrin [VerfasserIn] |
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| | Baumann, Ryan [VerfasserIn] |
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| | Dyckow, Julia [VerfasserIn] |
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| | Landefeld, James [VerfasserIn] |
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| | Kogl, Elva [VerfasserIn] |
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| | Madireddy, Lohith [VerfasserIn] |
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| | Loudermilk, Rita [VerfasserIn] |
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| | Eggers, Erica L [VerfasserIn] |
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| | Singh, Sneha [VerfasserIn] |
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| | Caillier, Stacy J [VerfasserIn] |
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| | Hauser, Stephen L [VerfasserIn] |
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| | Cree, Bruce A C [VerfasserIn] |
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| | Schirmer, Lucas [VerfasserIn] |
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| | Wilson, Michael R [VerfasserIn] |
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| | Baranzini, Sergio E [VerfasserIn] |
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| Titel: | Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis |
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| Verf.angabe: | Kicheol Kim, Anne-Katrin Pröbstel, Ryan Baumann, Julia Dyckow, James Landefeld, Elva Kogl, Lohith Madireddy, Rita Loudermilk, Erica L Eggers, Sneha Singh, Stacy J Caillier, Stephen L Hauser, Bruce AC Cree, UCSF MS-EPIC Team, Lucas Schirmer, Michael R Wilson and Sergio E Baranzini |
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| E-Jahr: | 2021 |
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| Jahr: | February 2021 |
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| Umfang: | 12 S. |
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| Fussnoten: | Gesehen am 17.06.2021 ; Published: 29 December 2020 |
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| Titel Quelle: | Enthalten in: Brain |
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| Ort Quelle: | Oxford : Oxford Univ. Press, 1878 |
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| Jahr Quelle: | 2021 |
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| Band/Heft Quelle: | 144(2021), 2, Seite 450-461 |
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| ISSN Quelle: | 1460-2156 |
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| 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. |
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| DOI: | doi:10.1093/brain/awaa421 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext: https://doi.org/10.1093/brain/awaa421 |
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| | DOI: https://doi.org/10.1093/brain/awaa421 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| K10plus-PPN: | 1760723703 |
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| Verknüpfungen: | → Zeitschrift |
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Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis / Kim, Kicheol [VerfasserIn]; February 2021 (Online-Ressource)
