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Brain Advance Access originally published online on May 30, 2008
Brain 2008 131(7):1722-1735; doi:10.1093/brain/awn105
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mitochondrial defects in acute multiple sclerosis lesions

Don Mahad1, Iryna Ziabreva1, Hans Lassmann2 and Douglas Turnbull1

1The Mitochondrial Research Group, University of Newcastle upon Tyne, UK and 2Centre for Brain Research, Medical University of Vienna, Austria

Correspondence to: Prof. Dr Hans Lassmann, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien Austria E-mail: hans.lassmann{at}meduniwien.ac.at

Multiple sclerosis is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the CNS. The structural and immunopathological patterns of demyelination suggest that different immune mechanisms may be involved in tissue damage. In a subtype of lesions, which are mainly found in patients with acute fulminant multiple sclerosis with Balo's type concentric sclerosis and in a subset of early relapsing remitting multiple sclerosis, the initial myelin changes closely resemble those seen in white matter stroke (WMS), suggesting a hypoxia-like tissue injury. Since mitochondrial injury may be involved in the pathogenesis of such lesions, we analysed a number of mitochondrial respiratory chain proteins in active lesions from acute multiple sclerosis and from WMS using immunohistochemistry. Functionally important defects of mitochondrial respiratory chain complex IV [cytochrome c oxidase (COX)] including its catalytic component (COX-I) are present in Pattern III but not in Pattern II multiple sclerosis lesions. The lack of immunohistochemically detected COX-I is apparent in oligodendrocytes, hypertrophied astrocytes and axons, but not in microglia. The profile of immunohistochemically detected mitochondrial respiratory chain complex subunits differs between multiple sclerosis and WMS. The findings suggest that hypoxia-like tissue injury in Pattern III multiple sclerosis lesions may be due to mitochondrial impairment.

Key Words: multiple sclerosis; Pattern III lesion; mitochondria; cytochrome c oxidase

Abbreviations: CNPase, cyclic nucleotide phosphodiesterase; COX, cytochrome c oxidase; LFB, Luxol fast blue; MAG, myelin associated glycoprotein; MBP, myelin basic protein; mtDNA, mitochondrial DNA; NO, nitric oxide; NWM, normal white matter; PLP, proteolipid protein; WMS, white matter stroke

Received February 22, 2008. Revised April 25, 2008. Accepted May 1, 2008.


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