High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease

@article{Bender2006HighLO,
  title={High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease},
  author={Andreas Bender and Kim J. Krishnan and Christopher M Morris and Geoffrey A. Taylor and Amy K. Reeve and Robert H. Perry and Evelyn Jaros and Joshua Hersheson and Joanne Betts and Thomas Klopstock and Robert W. Taylor and Doug M. Turnbull},
  journal={Nature Genetics},
  year={2006},
  volume={38},
  pages={515-517}
}
Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% ± 9.3%; individuals with Parkinson disease, 52.3% ± 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the… 
Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
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It is shown 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, and dysregulation of mtDNA homeostasis is a key process in the pathogenesis of neuronal loss in Parkinson disease.
Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons
Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA (mtDNA) molecules with deletions, we show that a high proportion of individual pigmented neurons in the
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It is shown for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases.
Detrimental deletions: mitochondria, aging and Parkinson's disease.
  • S. Biskup, D. Moore
  • Biology
    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 2006
TLDR
Two papers present clear evidence for a high burden of mitochondrial DNA deletions within substantia nigra neurons in aged individuals and individuals with PD, pointing towards a common pathway inevitably leading to neuronal dysfunction and death.
Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions
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There is a specific susceptibility of dopaminergic SN neurons to accumulate substantial amounts of mtDNA deletions, regardless of the underlying clinical phenotype, in brains from AD and PD patients.
Alpha‐synuclein pathology and Parkinsonism associated with POLG1 mutations and multiple mitochondrial DNA deletions
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Post mortem examination of the brain and skeletal muscle sample from a patient with multiple mtDNA deletions revealed features of mitochondrial myopathy with frequent muscle fibres deficient in the mtDNA-encoded cytochrome c oxidase (COX), some of which were hyperactive for nuclear DNA (nDNA) encoded succinate dehydrogenase (SDH).
Mitochondrial DNA deletions in mice in men: substantia nigra is much less affected in the mouse.
The Impact of Pathogenic Mitochondrial DNA Mutations on Substantia Nigra Neurons
TLDR
The finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones.
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References

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Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons
Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA (mtDNA) molecules with deletions, we show that a high proportion of individual pigmented neurons in the
Mitochondrial DNA mutations in human disease
TLDR
This review explores the advances that have been made and the areas in which future progress is likely in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer.
Premature ageing in mice expressing defective mitochondrial DNA polymerase
TLDR
The results provide a causative link between mtDNA mutations and ageing phenotypes in mammals by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase.
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Using PCR, we found that normal heart muscle and brain from adult human individuals contain low levels of a specific mitochondrial DNA deletion, previously found only in patients affected with
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TLDR
An assay to determine the relative amount of deleted mtDNA using real-time fluorescence PCR that detects the vast majority of deleted molecules, thus eliminating the need to develop specific probes and will further the understanding of the role of mtDNA mutations in human disease and ageing.
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