Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Citations Over TimeTop 10% of 2016 papers
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.
Related Papers
- → Dopaminergic neurons(2004)339 cited
- → Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease(2021)7 cited
- → LPS-induced degeneration of dopaminergic neurons of substantia nigra in rats(2004)17 cited
- → Expression of c-Jun in dopaminergic neurons of the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice(1997)33 cited
- LPS-induced Degeneration of Dopaminergic Neurons of Substantia Nigra in Rats(2004)