Document Detail


Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis.
MedLine Citation:
PMID:  22688405     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mitochondrial DNA deletions (∆-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 ∆-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 ∆-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 ∆-mtDNA in MS. Our findings establish clonal expansion of ∆-mtDNA as a feature relatively more prominent within the choroid plexus epithelium in MS than AD, PD or controls. We propose clonal expansion of ∆-mtDNA as a molecular link between inflammation and part of a delayed cellular energy failure in MS.
Authors:
Graham R Campbell; Yevgenya Kraytsberg; Kim J Krishnan; Nobuhiko Ohno; Iryna Ziabreva; Amy Reeve; Bruce D Trapp; Jia Newcombe; Richard Reynolds; Hans Lassmann; Konstantin Khrapko; Doug M Turnbull; Don J Mahad
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-12
Journal Detail:
Title:  Acta neuropathologica     Volume:  124     ISSN:  1432-0533     ISO Abbreviation:  Acta Neuropathol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-20     Completed Date:  2012-12-10     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0412041     Medline TA:  Acta Neuropathol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  209-20     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / genetics,  metabolism,  pathology
Brain / metabolism,  pathology
Choroid Plexus / metabolism*,  pathology
DNA, Mitochondrial / genetics*,  metabolism
Humans
Multiple Sclerosis / genetics*,  metabolism,  pathology
Neurons / metabolism,  pathology
Sequence Deletion*
Grant Support
ID/Acronym/Agency:
096919//Wellcome Trust; G-0909//Parkinson's UK; G0400074//Medical Research Council; G0502157//Medical Research Council; G0700718//Medical Research Council; G0800674//Medical Research Council; G0900652//Medical Research Council; G1100540//Medical Research Council; MC_G0802536//Medical Research Council; R01 AG019787/AG/NIA NIH HHS; //Biotechnology and Biological Sciences Research Council; //Wellcome Trust
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial
Comments/Corrections

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