title: Prodegenerative IκBα expression in oligodendroglial α-synuclein models of multiple system atrophy.
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 responses 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 elicited by 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 immunofluorescence microscopy and in situ hybridization 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 and NF-κB p65 in some oligodendrocytes containing glial cytoplasmic inclusions. Our data suggest that oligodendroglial IκBα expression and NF-κB are activated early in the course of MSA and their balance contributes to the decision of cellular demise. Favoring oligodendroglial NF-κB activation may represent a therapeutic strategy for this devastating disease.
authors.affiliation: Department of Biomedicine & Danish Research Institute of Translational Neuroscience-DANDRITE, University of Aarhus, Aarhus, Denmark.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Kragh
authors.affiliation: Neuroscience Research Australia, Sydney, NSW, Australia; University of New South Wales, Sydney, NSW, Australia.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gysbers
authors.affiliation: Department of Neurosciences and Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0624, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Neuroscience Research Australia, Sydney, NSW, Australia; University of New South Wales, Sydney, NSW, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: Murphy
authors.affiliation: Neuroscience Research Australia, Sydney, NSW, Australia; University of New South Wales, Sydney, NSW, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Department of Neurosciences and Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0624, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Biomedicine & Danish Research Institute of Translational Neuroscience-DANDRITE, University of Aarhus, Aarhus, Denmark. Electronic address: phj@biokemi.au.dk.
authors.forename: Poul Henning
authors.initials: PH
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000473:pathology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000473:pathology*; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia; D009836:Oligodendroglia / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010770:Phosphotransferases / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C492235:Cdk5r1 protein, rat; D020672:I-kappa B Proteins; D004676:Myelin Basic Protein; C000606204:NFKBIA protein, human; D009419:Nerve Tissue Proteins; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D000072000:NF-KappaB Inhibitor alpha; D010770:Phosphotransferases
keywords: IκBα; Multiple system atrophy; NF-κB; Oligodendrocytes; α-Synuclein