Artikel
The pro-apoptotic bcl-2 family member Puma but not Noxa is essential for cuprizone-induced oligodendroglial cell death
Suche in Medline nach
Autoren
Veröffentlicht: | 11. September 2012 |
---|
Gliederung
Text
Multiple sclerosis (MS) lesions are characterized by inflammation, demyelination and
oligodendroglial loss. The mechanisms leading to oligodendroglial cell death are still incompletely understood. Therefore, the aim of this study was the identification of the molecular pathways involved in oligodendroglial cell death. Using microarray analysis we identified the candidate genes Puma and Noxa as being upregulated during cuprizone induced demyelination in C57Bl/6J mice. Puma (p53 upregulated modulator of apoptosis) and Noxa (Latin for damage) are pro-apoptotic members of the BH3 (Bcl-2 homology 3)-only protein family. When feeding Puma deficient and wild type mice with 0.1% cuprizone in powdered chow, Puma deficient mice showed dramatically reduced numbers of apoptotic oligodendrocytes and activated microglia in the corpora callosa compared to wild type littermates. In contrast, Noxa deficient and wild type mice did not show a significant difference in cell death or microglial activation. In order to confirm these results as well as to validate that these effects originate from oligodendrocytes, oligodendrocyte precursor cells (OPCs) were cultured from Puma and Noxa deficient and wild type littermates using an immunopanning protocol. Puma deficient OPCs showed reduced cell death susceptibility under normal cell culture conditions as well as after staurosporine or nitric oxide induced cell death compared to wild type littermates. Additionally, a significant increase in myelin gene expression on mRNA level could be observed in Puma deficient oligodendrocytes compared to wild type cells. In contrast, Noxa deficient OPCs did not show a difference in cell viability or myelin gene expression. When examining microglia cells obtained from Puma deficient and wild type littermates that where stimulated with LPS/IFNγ, Puma deficient cells showed a slightly reduced inflammatory response on mRNA levels compared to wild type cells. Furthermore we analysed the expression of Puma in MS lesions and were able to detect Puma positive oligodendrocytes in normal appearing white matter (NAWM) as well as in MS lesions. In summary, our data demonstrate that Puma but not Noxa is essential for oligodendroglial cell death in cuprizone induced demyelination and might also play a role in oligodendroglial cell loss in MS.