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