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IkappaB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappaB in the central nervous system

Raasch, Jenni
Zeller, Nicolas
van Loo, Geert
Mildner, Alexander
Erny, Daniel
Knobeloch, Klaus-Peter
Bethea, John R
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Published in Brain. 2011, vol. 134, no. Pt 4, p. 1184-98
Abstract The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IκB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IκB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IκB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IκB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IκB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases.
Keywords AnimalsAstrocytes/cytology/metabolismBlotting, WesternCentral Nervous System/cytology/metabolismCuprizoneDemyelinating Diseases/chemically induced/metabolismI-kappa B Kinase/metabolismMiceMicroglia/cytology/metabolismMyelin Sheath/metabolismNF-kappa B/metabolismNerve Regeneration/physiologyOligodendroglia/metabolismReverse Transcriptase Polymerase Chain ReactionSignal Transduction/physiology
PMID: 21310728
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Research group La Sclérose en plaques (908)
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MERKLER, Doron et al. IkappaB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappaB in the central nervous system. In: Brain, 2011, vol. 134, n° Pt 4, p. 1184-98. doi: 10.1093/brain/awq359 https://archive-ouverte.unige.ch/unige:25336

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Deposited on : 2013-01-10

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