title: Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease.
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.
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Dölle
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Irene
authors.initials: I
authors.lastname: Flønes
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Gonzalo S
authors.identifier: 0000-0002-1766-4108
authors.initials: GS
authors.lastname: Nido
authors.affiliation: Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Biomedicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Nelson
authors.initials: N
authors.lastname: Osuagwu
authors.affiliation: Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.|Gade Laboratory for Pathology, Department of Clinical Medicine, Haukeland University Hospital and University of Bergen, 5021 Bergen, Norway.
authors.forename: Stine
authors.initials: S
authors.lastname: Kristoffersen
authors.affiliation: Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.|Gade Laboratory for Pathology, Department of Clinical Medicine, Haukeland University Hospital and University of Bergen, 5021 Bergen, Norway.
authors.forename: Peer K
authors.initials: PK
authors.lastname: Lilleng
authors.affiliation: Network for Medical Sciences, University of Stavanger, 4036 Stavanger, Norway.
authors.forename: Jan Petter
authors.initials: JP
authors.lastname: Larsen
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Ole-Bjørn
authors.initials: OB
authors.lastname: Tysnes
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Kristoffer
authors.identifier: 0000-0001-9381-1109
authors.initials: K
authors.lastname: Haugarvoll
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Laurence A
authors.identifier: 0000-0003-0988-276X
authors.initials: LA
authors.lastname: Bindoff
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.|Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Tzoulis
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D004272:DNA, Mitochondrial