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I kappa B kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappa B in the central nervous system

Jenni Raasch, Nicolas Zeller, Geert van Loo UGent, Doron Merkler, Alexander Mildner, Daniel Erny, Klaus-Peter Knobeloch, John R Bethea, Ari Waisman and Markus Knust, et al. (2011) BRAIN. 134(4). p.1184-1198
abstract
The I kappa B 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, I kappa B 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 I kappa B 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 I kappa B kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, I kappa B 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 I kappa B kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting I kappa B kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
cuprizone, multiple sclerosis, glia, NF-kappa B, BRAIN, INHIBITION, MICE, MYELINATION, ASTROCYTES, oligodendrocyte, demyelination, remyelination, SPINAL-CORD, NEURITE OUTGROWTH, MULTIPLE-SCLEROSIS, TRANSCRIPTION FACTORS, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
journal title
BRAIN
Brain
volume
134
issue
4
pages
1184 - 1198
Web of Science type
Article
Web of Science id
000289163300029
JCR category
CLINICAL NEUROLOGY
JCR impact factor
9.457 (2011)
JCR rank
5/190 (2011)
JCR quartile
1 (2011)
ISSN
0006-8950
DOI
10.1093/brain/awq359
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1261752
handle
http://hdl.handle.net/1854/LU-1261752
date created
2011-06-14 13:17:19
date last changed
2013-02-27 09:09:31
@article{1261752,
  abstract     = {The I kappa B 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, I kappa B 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 I kappa B 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 I kappa B kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, I kappa B 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 I kappa B kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting I kappa B kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases.},
  author       = {Raasch, Jenni and Zeller, Nicolas and van Loo, Geert and Merkler, Doron and Mildner, Alexander and Erny, Daniel and Knobeloch, Klaus-Peter and Bethea, John R and Waisman, Ari and Knust, Markus and Del Turco, Domenico and Deller, Thomas and Blank, Thomas and Priller, Josef and Bruck, Wolfgang and Pasparakis, Manolis and Prinz, Marco},
  issn         = {0006-8950},
  journal      = {BRAIN},
  keyword      = {cuprizone,multiple sclerosis,glia,NF-kappa B,BRAIN,INHIBITION,MICE,MYELINATION,ASTROCYTES,oligodendrocyte,demyelination,remyelination,SPINAL-CORD,NEURITE OUTGROWTH,MULTIPLE-SCLEROSIS,TRANSCRIPTION FACTORS,EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS},
  language     = {eng},
  number       = {4},
  pages        = {1184--1198},
  title        = {I kappa B kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappa B in the central nervous system},
  url          = {http://dx.doi.org/10.1093/brain/awq359},
  volume       = {134},
  year         = {2011},
}

Chicago
Raasch, Jenni, Nicolas Zeller, Geert van Loo, Doron Merkler, Alexander Mildner, Daniel Erny, Klaus-Peter Knobeloch, et al. 2011. “I Kappa B Kinase 2 Determines Oligodendrocyte Loss by Non-cell-autonomous Activation of NF-kappa B in the Central Nervous System.” Brain 134 (4): 1184–1198.
APA
Raasch, J., Zeller, N., van Loo, G., Merkler, D., Mildner, A., Erny, D., Knobeloch, K.-P., et al. (2011). I kappa B kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappa B in the central nervous system. BRAIN, 134(4), 1184–1198.
Vancouver
1.
Raasch J, Zeller N, van Loo G, Merkler D, Mildner A, Erny D, et al. I kappa B kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappa B in the central nervous system. BRAIN. 2011;134(4):1184–98.
MLA
Raasch, Jenni, Nicolas Zeller, Geert van Loo, et al. “I Kappa B Kinase 2 Determines Oligodendrocyte Loss by Non-cell-autonomous Activation of NF-kappa B in the Central Nervous System.” BRAIN 134.4 (2011): 1184–1198. Print.