title: Mitochondrial DNA homeostasis is essential for nigrostriatal integrity.
abstract: Mitochondrial involvement in the pathogenesis of Parkinson's disease has been suggested by multiple studies, but the mechanisms involved remain unresolved. Here, we sought to identify which mitochondrial defects are associated with degeneration of the nigrostriatal system. Nigrostriatal integrity was assessed in vivo by dopamine transporter (DAT) imaging in twenty-one patients with mitochondrial disorders of different molecular aetiology including: maternally inherited mitochondrial DNA (mtDNA) point mutations, primary single mtDNA deletions, nuclear-encoded disorders of mtDNA replication and maintenance due to mutations in POLG or C10orf2 (Twinkle), and mutations in other nuclear mitochondrial genes including the mitochondrial aspartyl-tRNA synthetase (DARS2) and ADCK3 genes. Patients with mitochondrial disease were compared with twenty patients with Parkinson's disease and eighteen controls. Nigrostriatal degeneration occurred exclusively in patients with defective mtDNA replication and maintenance. In these patients, nigrostriatal degeneration was progressive and at least as severe as in patients with advanced Parkinson's disease. None of the patients with other mitochondrial defects showed evidence of nigral involvement. Our findings demonstrate that dopaminergic neurons of the substantia nigra are specifically vulnerable to defective mtDNA replication/repair or quality control and not to primary point mutations of mtDNA. These results support the hypothesis that accumulating somatic mtDNA damage plays an important role in neurodegeneration.
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Norway. Electronic address: Charalampos.Tzoulis@nevro.uib.no.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Tzoulis
authors.affiliation: Centre for Nuclear Medicine/PET, Department of Radiology, Haukeland University Hospital, Bergen, Norway; Institute for Surgical Sciences, University of Bergen, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzlmüller
authors.affiliation: Centre for Nuclear Medicine/PET, Department of Radiology, Haukeland University Hospital, Bergen, Norway; Institute for Surgical Sciences, University of Bergen, Norway.
authors.forename: Martin
authors.initials: M
authors.lastname: Biermann
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Haugarvoll
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000473:pathology; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000473:pathology* / Q000503:physiopathology*; D013378:Substantia Nigra / Q000473:pathology*; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial
keywords: Neurodegeneration; POLG; Parkinson disease; Polymerase gamma; Substantia nigra