| First Author | Kragh CL | Year | 2014 |
| Journal | Neurobiol Dis | Volume | 63 |
| Pages | 171-83 | PubMed ID | 24361600 |
| Mgi Jnum | J:259600 | Mgi Id | MGI:6141888 |
| Doi | 10.1016/j.nbd.2013.12.002 | Citation | Kragh CL, et al. (2014) Prodegenerative IkappaBalpha expression in oligodendroglial alpha-synuclein models of multiple system atrophy. Neurobiol Dis 63:171-83 |
| abstractText | Multiple system atrophy is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of alpha-synuclein in oligodendrocytes. To understand how alpha-synuclein aggregates impact oligodendroglial homeostasis, we investigated an oligodendroglial cell model of alpha-synuclein dependent degeneration and identified responses linked to the NF-kappaB transcription factor stress system. Coexpression of human alpha-synuclein and the oligodendroglial protein p25alpha increased the expression of IkappaBalpha mRNA and protein early during the degenerative process and this was dependent on both aggregation and Ser129 phosphorylation of alpha-synuclein. This response was prodegenerative because blocking IkappaBalpha expression by siRNA rescued the cells. IkappaBalpha is an inhibitor of NF-kappaB and acts by binding and retaining NF-kappaB p65 in the cytoplasm. The protection obtained by silencing IkappaBalpha was accompanied by a strong increase in nuclear p65 translocation indicating that NF-kappaB activation protects against alpha-synuclein aggregate stress. In the cellular model, two different phenotypes were observed; degenerating cells retracting their microtubules and resilient cells tolerating the coexpression of alpha-synuclein and p25alpha. The resilient cells displayed a significant higher nuclear translocation of p65 and activation of the NF-kappaB system relied on stress elicited by aggregated and Ser129 phosphorylated alpha-synuclein. To validate the relationship between oligodendroglial alpha-synuclein expression and IkappaBalpha, we analyzed two different lines of transgenic mice expressing human alpha-synuclein under the control of the oligodendrocytic MBP promotor (intermediate-expresser line 1 and high-expresser line 29). IkappaBalpha mRNA expression was increased in both lines and immunofluorescence microscopy and in situ hybridization revealed that IkappaBalpha mRNA and protein is expressed in oligodendrocytes. IkappaBalpha mRNA expression was demonstrated prior to activation of microglia and astrocytes in line 1. Human brain tissue affected by MSA displayed increased expression of IkappaBalpha and NF-kappaB p65 in some oligodendrocytes containing glial cytoplasmic inclusions. Our data suggest that oligodendroglial IkappaBalpha expression and NF-kappaB are activated early in the course of MSA and their balance contributes to the decision of cellular demise. Favoring oligodendroglial NF-kappaB activation may represent a therapeutic strategy for this devastating disease. |
