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Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Immunohistochemistry for porin and PGC-1α in dopaminergic substantia nigra neurons of individuals with PD and controls.Representative sections are shown from three individuals with PD and three controls (Ctrl). There is no detectable difference in staining intensity or distribution between individuals with PD and controls. All pictures have been taken at × 400 magnification. Scale bars, 20 μm.
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f5: Immunohistochemistry for porin and PGC-1α in dopaminergic substantia nigra neurons of individuals with PD and controls.Representative sections are shown from three individuals with PD and three controls (Ctrl). There is no detectable difference in staining intensity or distribution between individuals with PD and controls. All pictures have been taken at × 400 magnification. Scale bars, 20 μm.

Mentions: To investigate whether the loss of wild-type mtDNA in the PD group reflects a defect of mtDNA maintenance specifically, or an overall defect in mitochondrial biogenesis, we investigated markers of mitochondrial mass and biogenesis in the substantia nigra by immunohistochemistry in situ, in brain sections from individuals with PD and healthy controls. Total mitochondrial mass was assessed using the mitochondrial membrane marker porin, and mitochondrial biogenesis signalling was assessed via the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), a transcription co-activator that regulates mitochondrial biogenesis. Morphometric analyses of the sections revealed no detectable difference in either intensity or cellular distribution of the porin or PGC-1α staining between individuals with PD and controls, suggesting no overt change in mitochondrial biogenesis signalling or total mass in dopaminergic neurons (Figs 5 and 6).


Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Immunohistochemistry for porin and PGC-1α in dopaminergic substantia nigra neurons of individuals with PD and controls.Representative sections are shown from three individuals with PD and three controls (Ctrl). There is no detectable difference in staining intensity or distribution between individuals with PD and controls. All pictures have been taken at × 400 magnification. Scale bars, 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121427&req=5

f5: Immunohistochemistry for porin and PGC-1α in dopaminergic substantia nigra neurons of individuals with PD and controls.Representative sections are shown from three individuals with PD and three controls (Ctrl). There is no detectable difference in staining intensity or distribution between individuals with PD and controls. All pictures have been taken at × 400 magnification. Scale bars, 20 μm.
Mentions: To investigate whether the loss of wild-type mtDNA in the PD group reflects a defect of mtDNA maintenance specifically, or an overall defect in mitochondrial biogenesis, we investigated markers of mitochondrial mass and biogenesis in the substantia nigra by immunohistochemistry in situ, in brain sections from individuals with PD and healthy controls. Total mitochondrial mass was assessed using the mitochondrial membrane marker porin, and mitochondrial biogenesis signalling was assessed via the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), a transcription co-activator that regulates mitochondrial biogenesis. Morphometric analyses of the sections revealed no detectable difference in either intensity or cellular distribution of the porin or PGC-1α staining between individuals with PD and controls, suggesting no overt change in mitochondrial biogenesis signalling or total mass in dopaminergic neurons (Figs 5 and 6).

View Article: PubMed Central - PubMed

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.

No MeSH data available.