Lookup NU author(s): Graham Campbell,
Dr Iryna Ziabreva,
Dr Amy Reeve,
Emeritus Professor Doug Turnbull,
Dr Don Mahad
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Mitochondrial DNA deletions (a dagger-mtDNA) have been implicated in the pathogenesis of Alzheimer's disease (AD), multiple sclerosis (MS) and Parkinson's disease (PD), as well as ageing. Clonal expansion of a dagger-mtDNA is the process by which a mutant mtDNA molecule increases to high levels within a single cell containing both wild-type and mutant mtDNA. Unlike in AD and PD, the diffuse inflammatory process in MS involves the choroid plexus, and mitochondria are exposed to reactive oxygen and nitrogen species over a prolonged period. We determined the extent of respiratory enzyme deficiency and a dagger-mtDNA at a single cell level within choroid plexus epithelial cells in MS as well as in AD, PD and controls. The respiratory enzyme-deficient (lacking complex IV and with intact complex II activity) cells were more prevalent within the choroid plexus in AD, MS and PD compared with controls. The main catalytic subunit of complex IV (subunit-I of cytochrome c oxidase) was lacking in significantly more respiratory enzyme-deficient cells in MS compared with AD, PD and controls. The single cell analysis showed a fourfold increase in the percentage of respiratory enzyme-deficient choroid plexus epithelial cells harbouring clonally expanded a dagger-mtDNA in MS. Our findings establish clonal expansion of a dagger-mtDNA as a feature relatively more prominent within the choroid plexus epithelium in MS than AD, PD or controls. We propose clonal expansion of a dagger-mtDNA as a molecular link between inflammation and part of a delayed cellular energy failure in MS.
Author(s): Campbell GR, Kraytsberg Y, Krishnan KJ, Ohno N, Ziabreva I, Reeve A, Trapp BD, Newcombe J, Reynolds R, Lassmann H, Khrapko K, Turnbull DM, Mahad DJ
Publication type: Article
Publication status: Published
Journal: Acta Neuropathologica
Print publication date: 01/08/2012
ISSN (print): 0001-6322
ISSN (electronic): 1432-0533
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