Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease

Christian Dölle, Irene Flønes, Gonzalo S. Nido, Hrvoje Miletic, Nelson Osuagwu, Stine Kristoffersen, Peer K. Lilleng, Jan Petter Larsen, Ole-Bjørn Tysnes, Kristoffer Haugarvoll, Laurence A. Bindoff and Charalampos Tzoulis ()
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Christian Dölle: Haukeland University Hospital
Irene Flønes: Haukeland University Hospital
Gonzalo S. Nido: Haukeland University Hospital
Hrvoje Miletic: Haukeland University Hospital
Nelson Osuagwu: Haukeland University Hospital
Stine Kristoffersen: Haukeland University Hospital
Peer K. Lilleng: Haukeland University Hospital
Jan Petter Larsen: Network for Medical Sciences, University of Stavanger
Ole-Bjørn Tysnes: Haukeland University Hospital
Kristoffer Haugarvoll: Haukeland University Hospital
Laurence A. Bindoff: Haukeland University Hospital
Charalampos Tzoulis: Haukeland University Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Increased somatic mitochondrial DNA (mtDNA) mutagenesis causes premature aging in mice, and mtDNA damage accumulates in the human brain with aging and neurodegenerative disorders such as Parkinson disease (PD). Here, we study the complete spectrum of mtDNA changes, including deletions, copy-number variation and point mutations, in single neurons from the dopaminergic substantia nigra and other brain areas of individuals with Parkinson disease and neurologically healthy controls. We show that in dopaminergic substantia nigra neurons of healthy individuals, mtDNA copy number increases with age, maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. This upregulation fails to occur in individuals with Parkinson disease, however, resulting in depletion of the wild-type mtDNA population. By contrast, neuronal mtDNA point mutational load is not increased in Parkinson disease. Our findings suggest that dysregulation of mtDNA homeostasis is a key process in the pathogenesis of neuronal loss in Parkinson disease.

Date: 2016
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DOI: 10.1038/ncomms13548

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