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Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity

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dc.contributor.author Belogurov A.
dc.contributor.author Kuzina E.
dc.contributor.author Kudriaeva A.
dc.contributor.author Kononikhin A.
dc.contributor.author Kovalchuk S.
dc.contributor.author Surina Y.
dc.contributor.author Smirnov I.
dc.contributor.author Lomakin Y.
dc.contributor.author Bacheva A.
dc.contributor.author Stepanov A.
dc.contributor.author Karpova Y.
dc.contributor.author Lyupina Y.
dc.contributor.author Kharybin O.
dc.contributor.author Melamed D.
dc.contributor.author Ponomarenko N.
dc.contributor.author Sharova N.
dc.contributor.author Nikolaev E.
dc.contributor.author Gabibov A.
dc.date.accessioned 2018-09-18T20:09:54Z
dc.date.available 2018-09-18T20:09:54Z
dc.date.issued 2015
dc.identifier.issn 0892-6638
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/137163
dc.description.abstract © The Author(s). Recent findings indicate that the ubiquitin-proteasome system is involved in the pathogenesis of cancer as well as autoimmune and several neurodegenerative diseases, and is thus a target for novel therapeutics. One disease that is related to aberrant protein degradation is multiple sclerosis, an autoimmune disorder involving the processing and presentation of myelin autoantigens that leads to the destruction of axons. Here, we show that brainderived proteasomes from SJL mice with experimental autoimmune encephalomyelitis (EAE) in an ubiquitinindependent manner generate significantly increased amounts of myelin basic protein peptides that induces cytotoxic lymphocytes to target mature oligodendrocytes ex vivo. Ten times enhanced release of immunogenic peptides by cerebral proteasomes from EAE-SJL mice is caused by a dramatic shift in the balance between constitutive and β1i<sup>high</sup> immunoproteasomes in the CNS of SJL mice with EAE. We found that during EAE, β1i is increased in resident CNS cells, whereas β5i is imported by infiltrating lymphocytes through the blood-brain barrier. Peptidyl epoxyketone specifically inhibits brain-derived β1i<sup>high</sup> immunoproteasomes in vitro (k<inf>obs</inf>/[I] = 240 M<sup>-1</sup>s<sup>-1</sup>), and at a dose of 0.5 mg/kg, it ameliorates ongoing EAE in vivo. Therefore, our findings provide novel insights into myelin metabolism in pathophysiologic conditions and reveal that the β1i subunit of the immunoproteasome is a potential target to treat autoimmune neurologic diseases.
dc.relation.ispartofseries FASEB Journal
dc.subject Antigen presentation
dc.subject Experimental autoimmune encephalomyelitis
dc.subject Immunoproteasome
dc.subject Multiple sclerosis
dc.subject Oligodendrocytes
dc.title Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity
dc.type Article
dc.relation.ispartofseries-issue 5
dc.relation.ispartofseries-volume 29
dc.collection Публикации сотрудников КФУ
dc.relation.startpage 1901
dc.source.id SCOPUS08926638-2015-29-5-SID84932640456


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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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