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Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis
Author(s) -
Campbell Graham R.,
Ziabreva Iryna,
Reeve Amy K.,
Krishnan Kim J.,
Reynolds Richard,
Howell Owen,
Lassmann Hans,
Turnbull Doug M.,
Mahad Don J.
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22109
Subject(s) - mitochondrial dna , biology , neurodegeneration , mitochondrial respiratory chain , respiratory chain , mitochondrion , multiple sclerosis , atrophy , amyotrophic lateral sclerosis , pathology , genetics , microbiology and biotechnology , gene , immunology , disease , medicine
Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases. Methods Ninety‐eight snap‐frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long‐range and real‐time PCR and sequencing were used to identify and analyze respiratory‐deficient neurons devoid of complex IV and with complex II activity. Results The density of respiratory‐deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory‐deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory‐deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single‐cell level. Furthermore, there were neurons lacking mtDNA‐encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory‐deficient neurons. Interpretation These findings provide evidence that neurons in MS are respiratory‐deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS. Ann Neurol 2010