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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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Ultra-deep mtDNA sequencing in single dopaminergic neurons of the substantia nigra.(a,b) Burden of mtDNA SNVs per neuron plotted against heteroplasmy frequency (HF). mtDNA point mutational burden is similar in individuals with PD and controls across the range of HF. Error bars show 95% confidence intervals (CIs). (c–e) Distribution and type of mtDNA SNVs in neurons of individuals with PD and controls. (c) Physical distribution of low-frequency SNVs (0.1–1%) on the sequenced mtDNA fragment in individuals with PD and controls. Each variant is represented by a vertical black streak to allow differentiation between areas with low mutation frequencies (lighter shade) to high-mutation frequencies (darker shade). mtDNA positions and physical gene location are shown in scale on the x axis. There is no significant difference in regional SNVs distribution between regions/genes or between individuals with PD and controls. (d) Ratio of mtDNA transitions to transversions (Ti/Tv) at low (0.001–0.01) and high (0.01–0.98) heteroplasmic frequencies. PD and controls show no difference in transition/transversion composition across heteroplasmic frequencies (χ2). (e) The proportion of G:C>T:A tranversions is similar in individuals with PD and controls. Error bars show 95% CIs.
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f8: Ultra-deep mtDNA sequencing in single dopaminergic neurons of the substantia nigra.(a,b) Burden of mtDNA SNVs per neuron plotted against heteroplasmy frequency (HF). mtDNA point mutational burden is similar in individuals with PD and controls across the range of HF. Error bars show 95% confidence intervals (CIs). (c–e) Distribution and type of mtDNA SNVs in neurons of individuals with PD and controls. (c) Physical distribution of low-frequency SNVs (0.1–1%) on the sequenced mtDNA fragment in individuals with PD and controls. Each variant is represented by a vertical black streak to allow differentiation between areas with low mutation frequencies (lighter shade) to high-mutation frequencies (darker shade). mtDNA positions and physical gene location are shown in scale on the x axis. There is no significant difference in regional SNVs distribution between regions/genes or between individuals with PD and controls. (d) Ratio of mtDNA transitions to transversions (Ti/Tv) at low (0.001–0.01) and high (0.01–0.98) heteroplasmic frequencies. PD and controls show no difference in transition/transversion composition across heteroplasmic frequencies (χ2). (e) The proportion of G:C>T:A tranversions is similar in individuals with PD and controls. Error bars show 95% CIs.

Mentions: The overall burden of heteroplasmic SNVs was similar in individuals with PD and controls (PD 31.63±10.31, controls 34.82±9.55 variants per neuron, P=0.8) across the range of HF (Fig. 8a,b). The physical distribution of variation showed no significant gene-specific, or other regional difference between PD and controls (Fig. 8c and Supplementary Table 3). The transition to transversion ratio (Ti/Tv) of heteroplasmic SNVs was similarly low in both groups (PD 2.27±1.63, controls 2.03±1.48, P=1) implying a high fraction of random mutation which resonated with the high proportion of somatic mutation among the heteroplasmic changes (Fig. 8d). The proportion of G:C to T:A transversions which are commonly associated with oxidative DNA damage15 was also similar in the two groups (PD 0.28±0.08, controls 0.32±0.09, P=0.6), implying that oxidative stress is not a major factor in somatic mtDNA mutagenesis in PD (Fig. 8e).


Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Ultra-deep mtDNA sequencing in single dopaminergic neurons of the substantia nigra.(a,b) Burden of mtDNA SNVs per neuron plotted against heteroplasmy frequency (HF). mtDNA point mutational burden is similar in individuals with PD and controls across the range of HF. Error bars show 95% confidence intervals (CIs). (c–e) Distribution and type of mtDNA SNVs in neurons of individuals with PD and controls. (c) Physical distribution of low-frequency SNVs (0.1–1%) on the sequenced mtDNA fragment in individuals with PD and controls. Each variant is represented by a vertical black streak to allow differentiation between areas with low mutation frequencies (lighter shade) to high-mutation frequencies (darker shade). mtDNA positions and physical gene location are shown in scale on the x axis. There is no significant difference in regional SNVs distribution between regions/genes or between individuals with PD and controls. (d) Ratio of mtDNA transitions to transversions (Ti/Tv) at low (0.001–0.01) and high (0.01–0.98) heteroplasmic frequencies. PD and controls show no difference in transition/transversion composition across heteroplasmic frequencies (χ2). (e) The proportion of G:C>T:A tranversions is similar in individuals with PD and controls. Error bars show 95% CIs.
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f8: Ultra-deep mtDNA sequencing in single dopaminergic neurons of the substantia nigra.(a,b) Burden of mtDNA SNVs per neuron plotted against heteroplasmy frequency (HF). mtDNA point mutational burden is similar in individuals with PD and controls across the range of HF. Error bars show 95% confidence intervals (CIs). (c–e) Distribution and type of mtDNA SNVs in neurons of individuals with PD and controls. (c) Physical distribution of low-frequency SNVs (0.1–1%) on the sequenced mtDNA fragment in individuals with PD and controls. Each variant is represented by a vertical black streak to allow differentiation between areas with low mutation frequencies (lighter shade) to high-mutation frequencies (darker shade). mtDNA positions and physical gene location are shown in scale on the x axis. There is no significant difference in regional SNVs distribution between regions/genes or between individuals with PD and controls. (d) Ratio of mtDNA transitions to transversions (Ti/Tv) at low (0.001–0.01) and high (0.01–0.98) heteroplasmic frequencies. PD and controls show no difference in transition/transversion composition across heteroplasmic frequencies (χ2). (e) The proportion of G:C>T:A tranversions is similar in individuals with PD and controls. Error bars show 95% CIs.
Mentions: The overall burden of heteroplasmic SNVs was similar in individuals with PD and controls (PD 31.63±10.31, controls 34.82±9.55 variants per neuron, P=0.8) across the range of HF (Fig. 8a,b). The physical distribution of variation showed no significant gene-specific, or other regional difference between PD and controls (Fig. 8c and Supplementary Table 3). The transition to transversion ratio (Ti/Tv) of heteroplasmic SNVs was similarly low in both groups (PD 2.27±1.63, controls 2.03±1.48, P=1) implying a high fraction of random mutation which resonated with the high proportion of somatic mutation among the heteroplasmic changes (Fig. 8d). The proportion of G:C to T:A transversions which are commonly associated with oxidative DNA damage15 was also similar in the two groups (PD 0.28±0.08, controls 0.32±0.09, P=0.6), implying that oxidative stress is not a major factor in somatic mtDNA mutagenesis in PD (Fig. 8e).

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