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Brain Advance Access published online on October 11, 2005
Brain, doi:10.1093/brain/awh627
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received March 31, 2005
Revised June 25, 2005
Accepted August 1, 2005

Article

Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor

Anna Jurewicz 1, Mariola Matysiak 1, Krzysztof Tybor 2, Lukasz Kilianek 3, Cedric S. Raine 4, and Krzysztof Selmaj 1*

1 Department of Neurology, Medical University of Lodz, Lodz, Poland
2 Department of Neurosurgery, Medical University of Lodz, Lodz, Poland
3 Nencki Institute of Experimental Biology, Warsaw
4 Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, NY, USA

* To whom correspondence should be addressed.
Krzysztof Selmaj, E-mail: kselmaj{at}afazja.am.lodz.pl


  Abstract

Tumour necrosis factor (TNF)-induced death of oligodendrocytes, the cell type targeted in multiple sclerosis, is mediated by TNF receptor p55 (TNFR-p55). The ligation of TNFR-p55 induces several signal transduction pathways; however, the precise mechanism involved in human oligodendrocyte (hOL) death is unknown. We defined that TNF-induced death of hOLs is non-caspase dependent, as evidenced by lack of generation of caspases 8, 1 and 3 active subunits; lack of cleavage of caspases 1 and 3 fluorogenic substrates; and lack of hOL death inhibition by the general caspase inhibitor, ZVAD.FMK. Electrophoresis of TNF-exposed hOL DNA revealed large-scale DNA fragmentation characteristic of apoptosis-inducing factor (AIF)-mediated cell death, and co-localization experiments showed that AIF translocation to the nucleus occurred upon exposure to TNF. AIF depletion by an antisense strategy prevented TNF-induced hOL death. These results indicate that TNF-induced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination.

Keywords: oligodendrocytes; apoptosis inducing factor; multiple sclerosis; cell death.
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