title: Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Institute of Ageing and Health, Mitochondrial Research Group, Newcastle University, Newcastle upon Tyne, UK.
authors: Graham R
authors: GR
authors: Campbell
authors: Iryna
authors: I
authors: Ziabreva
authors: Amy K
authors: AK
authors: Reeve
authors: Kim J
authors: KJ
authors: Krishnan
authors: Richard
authors: R
authors: Reynolds
authors: Owen
authors: O
authors: Howell
authors: Hans
authors: H
authors: Lassmann
authors: Doug M
authors: DM
authors: Turnbull
authors: Don J
authors: DJ
authors: Mahad
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004579:Electron Transport / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV