. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006 May;38(5):515-7. PubMed.


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  1. Two interesting papers recently published in Nature Genetics describe the discovery of somatically occurring deletions in the mitochondrial genome in single cells within the substantia nigra. The manuscript by Bender et al. shows that there is an unexpectedly high level of mtDNA deletions in individual cells of the substantia nigra of both people with PD and controls. These mutations were associated with a cytochrome c oxidase (COX) deficiency.
    The manuscript by Kraytsberg et al. also showed a COX deficiency in neurons with mtDNA deletions within the substantia nigra of subjects ranging in age from 33 to 102 years of age. The number of mtDNA deletions was significantly greater in aged subjects. Analysis of their cell types, such as Purkinje cells and pyramidal neurons, showed that these contained undetectable levels of mtDNA deletion.

    While the equivalent levels of mutation between PD and controls suggests that this type of mutation is not driving disease, it is hard to imagine that these mutations, which are associated with a significant reduction in COX activity, are not deleterious to the cell. While the data from Bender and colleagues suggest that these deletions are not driving the nigrostriatal dopaminergic dysfunction/degeneration seen in PD, one wonders if this is in part the key to the preferential vulnerability of this neuronal population.

    View all comments by Andrew Singleton
  2. These two new studies find that deletions in mitochondrial DNA (mtDNA) accumulate with aging, and are found at very high levels in dopamine-producing neurons within the substantia nigra. These are very important studies since they may account for the age-dependence of Parkinson disease (PD), and could play a central role in predisposing individuals to PD.

    The first of the two studies used a novel single molecule PCR approach to look at the total burden of mtDNA molecules with deletions in normal aging within the substantia nigra. It is well known that mitochondrial deletions and point mutations accumulate with normal aging. In tissue homogenates, however, they are of relatively low abundance. Their physiological significance has, therefore, been questioned. It had previously been shown by immunohistochemistry that a significant proportion of pigmented neurons in the substantia nigra show decreased cytochrome c oxidase activity.

    In the initial study, the authors examined mtDNA deletions in individual neurons of substantia nigra at various ages, and compared the mutational loads in the COX-positive and COX-deficient neurons. The authors found that there was a marked age-dependent accumulation of deletions within individual neurons. They were higher in COX-deficient as compared to COX-positive neurons. In many neurons, the fraction of deletions exceeded 60 percent, which is believed to be the phenotypic threshold above which mtDNA deletions impair respiratory function. The marked difference in distribution of mtDNA deletions between COX-positive and COX-deficient neurons implies that the mitochondrial deletions may be one of the primary causes of the COX defect. Three subunits of cytochrome c oxidase are encoded on mtDNA.

    In the second paper by Bender et al., the authors examined individual neurons in both aged and PD subjects. Once again, these studies were carried out on single neurons, which were dissected from substantia nigra. To identify the presence of mitochondrial respiratory chain defects, they performed dual histochemical analysis of both cytochrome c oxidase, and succinate dehydrogenase in the frozen midbrain sections. The neurons were laser microdissected. The DNA was examined for deletions using long-chain PCR, and also by a novel technique amplifying a segment of the mtDNA, which contains a subunit of complex 1 that is typically deleted by mtDNA deletions. The authors found age-dependent increases in mtDNA deletion with both normal aging and, to a greater extent, in PD. The overall level of deletions in the PD subjects was 52.3 +/- 9.3 versus 43.3 +/- 9.3 in aged controls. There was a small increase in deletions in the hippocampal neurons of subjects with PD as compared to controls.

    These studies are of great potential significance. Dopaminergic neurons in the substantia nigra may accumulate mtDNA deletions above the threshold for mitochondrial dysfunction, which then may lead to a loss of dopaminergic neurons, and ultimately to full-blown PD.

    These findings raise a number of interesting questions. One is, why is there a propensity for substantia nigra dopaminergic neurons to accumulate mtDNA deletions? This may be due to the high oxidative capacity, as well as the increased oxidative stress, which is known to occur within the substantia nigra. The reactive oxygen species produced by dopamine metabolism may cause mtDNA breaks, which then may lead to the deletions. The deletions, which were detected within individual neurons, were clonal. They, therefore, appear to have a replicative advantage. Overall, these studies provide further evidence linking mitochondrial dysfunction to PD pathogenesis. They may play a crucial link between normal aging and the risk of developing PD.

    View all comments by M. Flint Beal

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