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Nat Commun. 2016 Nov 22;7:13548. doi: 10.1038/ncomms13548.

Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease.

Author information

1
Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.
2
Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
3
Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.
4
Department of Biomedicine, University of Bergen, 5020 Bergen, Norway.
5
Gade Laboratory for Pathology, Department of Clinical Medicine, Haukeland University Hospital and University of Bergen, 5021 Bergen, Norway.
6
Network for Medical Sciences, University of Stavanger, 4036 Stavanger, Norway.

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.

PMID:
27874000
PMCID:
PMC5121427
DOI:
10.1038/ncomms13548
[Indexed for MEDLINE]
Free PMC Article

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