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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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Age-dependent mtDNA changes in three neuronal populations from neurologically healthy controls.Single neurons from three brain areas of neurologically healthy controls (n=21) were analysed for mtDNA copy number and deletion level.(a–c) Single dopaminergic neurons of the pars compacta of the substantia nigra (n=147). (d–f) Pyramidal neurons of the frontal cortex (n=193). (g–i) Purkinje cells of the cerebellum (n=148). All three areas were analysed from all subjects (n=21). (a) In the substantia nigra, the fraction (%) of mtDNA harbouring major arc deletions increases significantly with age (n=147, P=1 × 10−6; Pearson correlation). This is accompanied by a concomitant increase of mtDNA copy number (b), which correlates strongly with the levels of mtDNA deletion in each neuron (n=147, P=2 × 10−6; Pearson correlation) (c). Frontal neurons show no increase in mtDNA deletion levels (n=193, r=−0.20, P=0.06; Pearson correlation) (d) or copy number (n=193, r=0.11, P=0.14; Pearson correlation) (e) with age and no correlation between mtDNA copy number and levels of mtDNA deletion (n=193, r=−0.12, P=0.09; Pearson correlation) (f). Similarly, Purkinje cells of the cerebellum show no increase in mtDNA deletion levels (n=148, r=−0.10, P=0.21; Pearson correlation) (g) or copy number (n=148, r=0.12, P=0.16; Pearson correlation) (h) with age and mtDNA copy number does not correlate with the levels of mtDNA deletion (n=148, r=−0.09, P=0.28; Pearson correlation) (i). Each dot represents data from a single neuron. Statistics are derived from Pearson correlation and linear regression analyses.
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f2: Age-dependent mtDNA changes in three neuronal populations from neurologically healthy controls.Single neurons from three brain areas of neurologically healthy controls (n=21) were analysed for mtDNA copy number and deletion level.(a–c) Single dopaminergic neurons of the pars compacta of the substantia nigra (n=147). (d–f) Pyramidal neurons of the frontal cortex (n=193). (g–i) Purkinje cells of the cerebellum (n=148). All three areas were analysed from all subjects (n=21). (a) In the substantia nigra, the fraction (%) of mtDNA harbouring major arc deletions increases significantly with age (n=147, P=1 × 10−6; Pearson correlation). This is accompanied by a concomitant increase of mtDNA copy number (b), which correlates strongly with the levels of mtDNA deletion in each neuron (n=147, P=2 × 10−6; Pearson correlation) (c). Frontal neurons show no increase in mtDNA deletion levels (n=193, r=−0.20, P=0.06; Pearson correlation) (d) or copy number (n=193, r=0.11, P=0.14; Pearson correlation) (e) with age and no correlation between mtDNA copy number and levels of mtDNA deletion (n=193, r=−0.12, P=0.09; Pearson correlation) (f). Similarly, Purkinje cells of the cerebellum show no increase in mtDNA deletion levels (n=148, r=−0.10, P=0.21; Pearson correlation) (g) or copy number (n=148, r=0.12, P=0.16; Pearson correlation) (h) with age and mtDNA copy number does not correlate with the levels of mtDNA deletion (n=148, r=−0.09, P=0.28; Pearson correlation) (i). Each dot represents data from a single neuron. Statistics are derived from Pearson correlation and linear regression analyses.

Mentions: First we characterized age-dependent mtDNA changes in different neuronal populations from 21 controls aged 11–87 years (Supplementary Table 1). We studied single dopaminergic neurons from the ventrolateral tier (area A9) of the substantia nigra pars compacta, pyramidal neurons from the frontal cortex and Purkinje cells of the cerebellar cortex (Fig. 1). The proportion of mtDNA molecules harbouring major arc deletions showed a significant positive correlation with age in nigral neurons (r=0.39, P=1 × 10−6; Fig. 2a), which is in line with previous reports45. Total mtDNA copy number also increased with age (r=0.29, P=4 × 10−4; Fig. 2b) and, strikingly, showed a significant positive correlation with the level of deletion in each neuron (r=0.40, P=2 × 10−6; Fig. 2c). Due to this concomitant copy number increase, absolute levels of wild-type (non-deleted) mtDNA did not decrease over time (r=0.03, P=0.3) in spite of progressively increasing proportion of deletion. Whereas both deletion and age appeared to correlate with mtDNA copy number, using a multiple linear regression model, we found that only deletion was a statistically significant predictor of copy number (model: r=0.40, R2=0.18, P=6.3 × 10−7; deletion: β=0.34, P=6 × 10−5; age: β=0.16, P=0.06).


Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Age-dependent mtDNA changes in three neuronal populations from neurologically healthy controls.Single neurons from three brain areas of neurologically healthy controls (n=21) were analysed for mtDNA copy number and deletion level.(a–c) Single dopaminergic neurons of the pars compacta of the substantia nigra (n=147). (d–f) Pyramidal neurons of the frontal cortex (n=193). (g–i) Purkinje cells of the cerebellum (n=148). All three areas were analysed from all subjects (n=21). (a) In the substantia nigra, the fraction (%) of mtDNA harbouring major arc deletions increases significantly with age (n=147, P=1 × 10−6; Pearson correlation). This is accompanied by a concomitant increase of mtDNA copy number (b), which correlates strongly with the levels of mtDNA deletion in each neuron (n=147, P=2 × 10−6; Pearson correlation) (c). Frontal neurons show no increase in mtDNA deletion levels (n=193, r=−0.20, P=0.06; Pearson correlation) (d) or copy number (n=193, r=0.11, P=0.14; Pearson correlation) (e) with age and no correlation between mtDNA copy number and levels of mtDNA deletion (n=193, r=−0.12, P=0.09; Pearson correlation) (f). Similarly, Purkinje cells of the cerebellum show no increase in mtDNA deletion levels (n=148, r=−0.10, P=0.21; Pearson correlation) (g) or copy number (n=148, r=0.12, P=0.16; Pearson correlation) (h) with age and mtDNA copy number does not correlate with the levels of mtDNA deletion (n=148, r=−0.09, P=0.28; Pearson correlation) (i). Each dot represents data from a single neuron. Statistics are derived from Pearson correlation and linear regression analyses.
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Related In: Results  -  Collection

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f2: Age-dependent mtDNA changes in three neuronal populations from neurologically healthy controls.Single neurons from three brain areas of neurologically healthy controls (n=21) were analysed for mtDNA copy number and deletion level.(a–c) Single dopaminergic neurons of the pars compacta of the substantia nigra (n=147). (d–f) Pyramidal neurons of the frontal cortex (n=193). (g–i) Purkinje cells of the cerebellum (n=148). All three areas were analysed from all subjects (n=21). (a) In the substantia nigra, the fraction (%) of mtDNA harbouring major arc deletions increases significantly with age (n=147, P=1 × 10−6; Pearson correlation). This is accompanied by a concomitant increase of mtDNA copy number (b), which correlates strongly with the levels of mtDNA deletion in each neuron (n=147, P=2 × 10−6; Pearson correlation) (c). Frontal neurons show no increase in mtDNA deletion levels (n=193, r=−0.20, P=0.06; Pearson correlation) (d) or copy number (n=193, r=0.11, P=0.14; Pearson correlation) (e) with age and no correlation between mtDNA copy number and levels of mtDNA deletion (n=193, r=−0.12, P=0.09; Pearson correlation) (f). Similarly, Purkinje cells of the cerebellum show no increase in mtDNA deletion levels (n=148, r=−0.10, P=0.21; Pearson correlation) (g) or copy number (n=148, r=0.12, P=0.16; Pearson correlation) (h) with age and mtDNA copy number does not correlate with the levels of mtDNA deletion (n=148, r=−0.09, P=0.28; Pearson correlation) (i). Each dot represents data from a single neuron. Statistics are derived from Pearson correlation and linear regression analyses.
Mentions: First we characterized age-dependent mtDNA changes in different neuronal populations from 21 controls aged 11–87 years (Supplementary Table 1). We studied single dopaminergic neurons from the ventrolateral tier (area A9) of the substantia nigra pars compacta, pyramidal neurons from the frontal cortex and Purkinje cells of the cerebellar cortex (Fig. 1). The proportion of mtDNA molecules harbouring major arc deletions showed a significant positive correlation with age in nigral neurons (r=0.39, P=1 × 10−6; Fig. 2a), which is in line with previous reports45. Total mtDNA copy number also increased with age (r=0.29, P=4 × 10−4; Fig. 2b) and, strikingly, showed a significant positive correlation with the level of deletion in each neuron (r=0.40, P=2 × 10−6; Fig. 2c). Due to this concomitant copy number increase, absolute levels of wild-type (non-deleted) mtDNA did not decrease over time (r=0.03, P=0.3) in spite of progressively increasing proportion of deletion. Whereas both deletion and age appeared to correlate with mtDNA copy number, using a multiple linear regression model, we found that only deletion was a statistically significant predictor of copy number (model: r=0.40, R2=0.18, P=6.3 × 10−7; deletion: β=0.34, P=6 × 10−5; age: β=0.16, P=0.06).

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