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.
Highlights
Increased somatic mitochondrial DNA mutagenesis causes premature aging in mice, and mtDNA damage accumulates in the human brain with aging and neurodegenerative disorders such as Parkinson disease (PD)
In this work, we characterize the complete spectrum of neuronal mtDNA changes in aging and PD, and measure the range of mtDNA damage in the same neuron
We show that dynamic regulation of mtDNA copy number occurs in aging substantia nigra neurons allowing them to maintain their pool of wild-type mtDNA in spite of Number of single-nucleotide variants (SNVs) / 1,000 bp a 25
Summary
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). 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. The dopaminergic substantia nigra is susceptible to somatic mtDNA deletions, which accumulate there at substantially higher levels compared with other brainstem nuclei, deep grey structures, or the cerebral and cerebellar cortex This predilection has led to the hypothesis that mtDNA damage plays a role in the pathogenesis of Parkinson disease (PD)[4,5], where neurodegeneration of the substantia nigra is the main pathological hallmark and widely accepted as the cause of the cardinal clinical features. Our findings suggest that mtDNA homeostasis is impaired in the substantia nigra of individuals with PD
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