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Mitochondrial DNA Deletions and Neurodegeneration in Multiple Sclerosis

Lookup NU author(s): Graham Campbell, Dr Iryna Ziabreva, Dr Amy Reeve, Kim Krishnan, Emeritus Professor Doug Turnbull, Dr Don Mahad

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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. 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 2011;69:481-492


Publication metadata

Author(s): Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ

Publication type: Article

Publication status: Published

Journal: Annals of Neurology

Year: 2011

Volume: 69

Issue: 3

Pages: 481-492

Print publication date: 08/11/2011

ISSN (print): 0364-5134

ISSN (electronic): 1531-8249

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/ana.22109

DOI: 10.1002/ana.22109


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