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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.

SUBMITTER: Dolle C

PROVIDER: S-EPMC5121427 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other

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

Dölle Christian C Flønes Irene I Nido Gonzalo S GS Miletic Hrvoje H Osuagwu Nelson N Kristoffersen Stine S Lilleng Peer K PK Larsen Jan Petter JP Tysnes Ole-Bjørn OB Haugarvoll Kristoffer K Bindoff Laurence A LA Tzoulis Charalampos C

Nature communications 20161122

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 ...[more]

PMID: 27874000

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Project description:Background Motor symptoms in Parkinson disease (PD) have exhibited lateral asymmetry, suggesting asymmetric neuronal loss in the substantia nigra (SN). Diffusion MRI may be able to help confirm tissue microstructural alterations in the substantia nigra to probe for the presence of asymmetry. Purpose To investigate lateral asymmetry in the SN of patients with PD by using diffusion MRI with both Gaussian and non-Gaussian models. Materials and Methods In this cross-sectional study conducted from March 2015 to March 2017, 27 participants with PD and 27 age-matched healthy control (HC) participants, all right handed, underwent MRI at 3.0 T. High-spatial-resolution diffusion images were acquired with a reduced field of view by using seven b values up to 3000 sec/mm2. A continuous-time random-walk (CTRW) non-Gaussian diffusion model was used to produce anomalous diffusion coefficient (Dm) and temporal (α) and spatial (β) diffusion heterogeneity indexes followed by a Gaussian diffusion model to yield an apparent diffusion coefficient (ADC). Individual or linear combinations of diffusion parameters in the SN were unilaterally and bilaterally compared between the PD and HC groups. Results In the bilateral comparison between the PD and HC groups, differences were observed in β (0.67 ± 0.06 [standard deviation] vs 0.64 ± 0.04, respectively; P = .016), ADC (0.48 μm2/msec ± 0.08 vs 0.53 μm2/msec ± 0.06, respectively; P = .03), and the combination of CTRW parameters (P = .02). In the unilateral comparison, differences were observed in all diffusion parameters on the left SN (P < .03), but not on the right (P > .20). In a receiver operating characteristic (ROC) analysis to delineate left SN abnormality in PD, the combination of Dm, α, and β produced the best sensitivity (sensitivity, 0.78); the combination of Dm and β produced the best specificity (specificity, 0.85); and the combination of α and β produced the largest area under the ROC curve (area under the ROC curve, 0.73). Conclusion These results suggest that quantitative diffusion MRI is sensitive to brain tissue changes in participants with Parkinson disease and provide evidence of substantia nigra lateral asymmetry in this disease. © RSNA, 2019 Online supplemental material is available for this article.

Dataset Information

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

Publications

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

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