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Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease

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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.

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Impaired mtDNA maintenance in the dopaminergic substantia nigra of patients with PD.Data show analyses in single dopaminergic substantia nigra neurons from individuals with PD (n=84 neurons from 10 individuals) and age-matched controls (n=74 neurons from 10 individuals). (a) Deletion levels are significantly higher in PD compared with controls (P=0.004; Mann–Whitney U test). Error bars show s.d. (b) Scatter plot of total and wild-type (non-deleted) mtDNA. Total mtDNA copy number is similar in PD and controls, but the levels of wild-type mtDNA are significantly decreased in PD (P=0.006; Mann–Whitney U test). Bars show mean. (c,d) Linear regression of neuronal mtDNA copy number plotted against deletion levels; each point shows data from a single neuron. The correlation between mtDNA copy number and deletion is poor in PD (P=0.04, r=0.22) compared with controls (P=5 × 10−5, r=0.50; Pearson correlation). (e) Fraction of total dopaminergic substantia nigra neurons of individuals with PD and controls distributed according to wild-type (non-deleted) mtDNA content. The fraction of neurons with very low (<10,000) wild-type mtDNA copy number is significantly enriched in PD (Ctrl 2.7% versus PD 14.3%, P=0.01; Fisher's exact test), whereas in controls, the majority of neurons contain at least 15,000 copies of non-deleted mtDNA. Ctrl: controls. *P<0.05, **P<0.01.
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f3: Impaired mtDNA maintenance in the dopaminergic substantia nigra of patients with PD.Data show analyses in single dopaminergic substantia nigra neurons from individuals with PD (n=84 neurons from 10 individuals) and age-matched controls (n=74 neurons from 10 individuals). (a) Deletion levels are significantly higher in PD compared with controls (P=0.004; Mann–Whitney U test). Error bars show s.d. (b) Scatter plot of total and wild-type (non-deleted) mtDNA. Total mtDNA copy number is similar in PD and controls, but the levels of wild-type mtDNA are significantly decreased in PD (P=0.006; Mann–Whitney U test). Bars show mean. (c,d) Linear regression of neuronal mtDNA copy number plotted against deletion levels; each point shows data from a single neuron. The correlation between mtDNA copy number and deletion is poor in PD (P=0.04, r=0.22) compared with controls (P=5 × 10−5, r=0.50; Pearson correlation). (e) Fraction of total dopaminergic substantia nigra neurons of individuals with PD and controls distributed according to wild-type (non-deleted) mtDNA content. The fraction of neurons with very low (<10,000) wild-type mtDNA copy number is significantly enriched in PD (Ctrl 2.7% versus PD 14.3%, P=0.01; Fisher's exact test), whereas in controls, the majority of neurons contain at least 15,000 copies of non-deleted mtDNA. Ctrl: controls. *P<0.05, **P<0.01.

Mentions: We next investigated the integrity of neuronal mtDNA homeostasis in single neurons from individuals with validated sporadic PD (n=10) compared with neurologically healthy age- and sex-matched controls (n=10; Supplementary Table 1). Dopaminergic nigral neurons from individuals with PD contained significantly higher levels of mtDNA deletions than nigral neurons from healthy controls (PD mean 40.2±20.0%, controls mean 31.5±19.5%, P=0.004; Fig. 3a). Notably, the proportion of neurons with deletion levels exceeding 60%, which has been postulated as a threshold for respiratory dysfunction in cells13, was twice as high in the PD group (21.4%, n=84) compared with controls (10.8%, n=74).


Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Impaired mtDNA maintenance in the dopaminergic substantia nigra of patients with PD.Data show analyses in single dopaminergic substantia nigra neurons from individuals with PD (n=84 neurons from 10 individuals) and age-matched controls (n=74 neurons from 10 individuals). (a) Deletion levels are significantly higher in PD compared with controls (P=0.004; Mann–Whitney U test). Error bars show s.d. (b) Scatter plot of total and wild-type (non-deleted) mtDNA. Total mtDNA copy number is similar in PD and controls, but the levels of wild-type mtDNA are significantly decreased in PD (P=0.006; Mann–Whitney U test). Bars show mean. (c,d) Linear regression of neuronal mtDNA copy number plotted against deletion levels; each point shows data from a single neuron. The correlation between mtDNA copy number and deletion is poor in PD (P=0.04, r=0.22) compared with controls (P=5 × 10−5, r=0.50; Pearson correlation). (e) Fraction of total dopaminergic substantia nigra neurons of individuals with PD and controls distributed according to wild-type (non-deleted) mtDNA content. The fraction of neurons with very low (<10,000) wild-type mtDNA copy number is significantly enriched in PD (Ctrl 2.7% versus PD 14.3%, P=0.01; Fisher's exact test), whereas in controls, the majority of neurons contain at least 15,000 copies of non-deleted mtDNA. Ctrl: controls. *P<0.05, **P<0.01.
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f3: Impaired mtDNA maintenance in the dopaminergic substantia nigra of patients with PD.Data show analyses in single dopaminergic substantia nigra neurons from individuals with PD (n=84 neurons from 10 individuals) and age-matched controls (n=74 neurons from 10 individuals). (a) Deletion levels are significantly higher in PD compared with controls (P=0.004; Mann–Whitney U test). Error bars show s.d. (b) Scatter plot of total and wild-type (non-deleted) mtDNA. Total mtDNA copy number is similar in PD and controls, but the levels of wild-type mtDNA are significantly decreased in PD (P=0.006; Mann–Whitney U test). Bars show mean. (c,d) Linear regression of neuronal mtDNA copy number plotted against deletion levels; each point shows data from a single neuron. The correlation between mtDNA copy number and deletion is poor in PD (P=0.04, r=0.22) compared with controls (P=5 × 10−5, r=0.50; Pearson correlation). (e) Fraction of total dopaminergic substantia nigra neurons of individuals with PD and controls distributed according to wild-type (non-deleted) mtDNA content. The fraction of neurons with very low (<10,000) wild-type mtDNA copy number is significantly enriched in PD (Ctrl 2.7% versus PD 14.3%, P=0.01; Fisher's exact test), whereas in controls, the majority of neurons contain at least 15,000 copies of non-deleted mtDNA. Ctrl: controls. *P<0.05, **P<0.01.
Mentions: We next investigated the integrity of neuronal mtDNA homeostasis in single neurons from individuals with validated sporadic PD (n=10) compared with neurologically healthy age- and sex-matched controls (n=10; Supplementary Table 1). Dopaminergic nigral neurons from individuals with PD contained significantly higher levels of mtDNA deletions than nigral neurons from healthy controls (PD mean 40.2±20.0%, controls mean 31.5±19.5%, P=0.004; Fig. 3a). Notably, the proportion of neurons with deletion levels exceeding 60%, which has been postulated as a threshold for respiratory dysfunction in cells13, was twice as high in the PD group (21.4%, n=84) compared with controls (10.8%, n=74).

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.


Related in: MedlinePlus