Publication:
Prodegenerative IκBα expression in oligodendroglial α-synuclein models of multiple system atrophy

dc.contributor.author Kragh, Christine L en_US
dc.contributor.author Gysbers, Amanda M en_US
dc.contributor.author Rockenstein, Edward en_US
dc.contributor.author Murphy, Karen en_US
dc.contributor.author Halliday, Glenda en_US
dc.contributor.author Masliah, Eliezer en_US
dc.contributor.author Jensen, Poul Henning en_US
dc.date.accessioned 2021-11-25T12:29:25Z
dc.date.available 2021-11-25T12:29:25Z
dc.date.issued 2014 en_US
dc.description.abstract Multiple system atrophy is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of α-synuclein in oligodendrocytes. To understand how α-synuclein aggregates impact oligodendroglial homeostasis, we investigated an oligodendroglial cell model of α-synuclein dependent degeneration and identified responsive genes linked to the NF-κB transcription factor stress system. Coexpression of human α-synuclein and the oligodendroglial protein p25α increased the expression of IκBα mRNA and protein early during the degenerative process and this was dependent on both aggregation and Ser129 phosphorylation of α-synuclein. This response was prodegenerative because blocking IκBα expression by siRNA rescued the cells. IκBα is an inhibitor of NF-κB and acts by binding and retaining NF-κB p65 in the cytoplasm. The protection obtained by silencing IκBα was accompanied by a strong increase in nuclear p65 translocation indicating that NF-κB activation protects against α-synuclein aggregate stress. In the cellular model, two different phenotypes were observed; degenerating cells retracting their microtubules and resilient cells tolerating the coexpression of α-synuclein and p25α. The resilient cells displayed a significant higher nuclear translocation of p65 and activation of the NF-κB system relied on stress from aggregated and Ser129 phosphorylated α-synuclein. To validate the relationship between oligodendroglial α-synuclein expression and IκBα, we analyzed two different lines of transgenic mice expressing human α-synuclein under the control of the oligodendrocytic MBP promotor (intermediate-expresser line 1 and high-expresser line 29). IκBα mRNA expression was increased in both lines and in situ hybridization and immunofluorescense microscopy revealed that IκBα mRNA and protein is expressed in oligodendrocytes. IκBα mRNA expression was demonstrated prior to activation of microglia and astrocytes in line 1. Human brain tissue affected by MSA displayed increased expression of IκBα in reactive astrocytes and in some oligodendrocytes containing glial cytoplasmic inclusions. Our data suggest that oligodendroglial IκBα expression is activated early in the course of MSA and contributes to the cellular demise. Favoring oligodendroglial NF-κB activation may represent a therapeutic strategy for this devastating disease. en_US
dc.identifier.issn 0969-9961 en_US
dc.identifier.uri http://hdl.handle.net/1959.4/53617
dc.language English
dc.language.iso EN en_US
dc.rights CC BY-NC-ND 3.0 en_US
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/3.0/au/ en_US
dc.source Legacy MARC en_US
dc.subject.other oligodendrocytes en_US
dc.subject.other Multiple system atrophy en_US
dc.subject.other α-synuclein en_US
dc.subject.other NF-κB en_US
dc.subject.other IκBα en_US
dc.title Prodegenerative IκBα expression in oligodendroglial α-synuclein models of multiple system atrophy en_US
dc.type Journal Article en
dcterms.accessRights open access
dspace.entity.type Publication en_US
unsw.accessRights.uri https://purl.org/coar/access_right/c_abf2
unsw.description.publisherStatement NOTICE: this is the author’s version of a work that was accepted for publication in Neurobiology of Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neurobiology of Disease, Vol. 63, March Issue, (2014) DOI 10.1016/j.nbd.2013 en_US
unsw.identifier.doiPublisher http://dx.doi.org/10.1016/j.nbd.2013.12.002 en_US
unsw.relation.faculty Medicine & Health
unsw.relation.ispartofissue March en_US
unsw.relation.ispartofjournal Neurobiology of Disease en_US
unsw.relation.ispartofpagefrompageto 171-183 en_US
unsw.relation.ispartofvolume 63 en_US
unsw.relation.originalPublicationAffiliation Kragh, Christine L, Department of Biomedicine, University of Aarhus, Aarhus, Denmark en_US
unsw.relation.originalPublicationAffiliation Gysbers, Amanda M, Neuroscience Research Australia, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Rockenstein, Edward, Department of Neurosciences and Pathology, University of California, San Diego, School of Medicine, La Jolla, California en_US
unsw.relation.originalPublicationAffiliation Murphy, Karen, Neuroscience Research Australia, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Halliday, Glenda, Neuroscience Research Australia, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Masliah, Eliezer, Department of Neurosciences and Pathology, University of California, San Diego, School of Medicine, La Jolla, California en_US
unsw.relation.originalPublicationAffiliation Jensen, Poul Henning, Department of Biomedicine, University of Aarhus, Aarhus, Denmark en_US
unsw.relation.school Neuroscience Research Australia *
unsw.subject.fieldofresearchcode 110903 Central Nervous System en_US
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