Potential conflict of interest:
Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis
Article first published online: 8 NOV 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 69, Issue 3, pages 481–492, March 2011
How to Cite
Campbell, G. R., Ziabreva, I., Reeve, A. K., Krishnan, K. J., Reynolds, R., Howell, O., Lassmann, H., Turnbull, D. M. and Mahad, D. J. (2011), Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol., 69: 481–492. doi: 10.1002/ana.22109
- Issue published online: 28 MAR 2011
- Article first published online: 8 NOV 2010
- Manuscript Accepted: 28 MAY 2010
- Manuscript Revised: 26 MAY 2010
- Manuscript Received: 21 FEB 2010
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.
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.
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.
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