Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515-517

Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
Nature Genetics (Impact Factor: 29.35). 06/2006; 38(5):515-7. DOI: 10.1038/ng1769
Source: PubMed


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 selective neuronal loss observed in brain aging and in Parkinson disease.

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Available from: Christopher M Morris, May 06, 2014
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    • "Furthermore, several relatively common aging-related diseases appear to have a mitochondrial component. For example, mitochondrial dysfunction is a hallmark of b-amyloidinduced neural toxicity in Alzheimer's disease (Lustbader et al. 2004; Tillement et al. 2011); Parkinson's disease patients, as well as elderly individuals, have the burden of mtDNA deletions within substantia nigra neurons (Bender et al. 2006; Kraytsberg et al. 2006); cardiovascular disease is associated with increased production of ROS in mitochondria, accumulation of mtDNA damage, and progressive respiratory chain dysfunction (Madamanchi and Runge 2007; Mercer et al. 2010); and mitochondrial dysfunction characterized by reduced ATP generation appears to have a causal role in features of type 2 diabetes (insulin resistance and hyperglycemia ) (Lowell and Shulman 2005). Declining mitochondrial function over the lifetime of an organism has been shown by several lines of evidence (Corral-Debrinski et al. 1992; Vendelbo and Nair 2011; Chistiakov et al. 2014). "
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    ABSTRACT: Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.
    Cold Spring Harbor Perspectives in Medicine 09/2015; 5(10). DOI:10.1101/cshperspect.a025130 · 9.47 Impact Factor
    • "In the Mutator Parkin-KO mice, the enzyme defects in complexes I and III correlate with the two mitochondrial-encoded genes with the worst MutPred scores relative to wild-type mice (Figures 4E and 4F). Thus, Mutator Parkin-KO mice not only display specific degeneration of the DA neurons but also biochemically mimic PD in humans (Bender et al., 2006; Schapira et al., 1989, 1990a). "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. PARK2 mutations cause early-onset forms of PD. PARK2 encodes an E3 ubiquitin ligase, Parkin, that can selectively translocate to dysfunctional mitochondria to promote their removal by autophagy. However, Parkin knockout (KO) mice do not display signs of neurodegeneration. To assess Parkin function in vivo, we utilized a mouse model that accumulates dysfunctional mitochondria caused by an accelerated generation of mtDNA mutations (Mutator mice). In the absence of Parkin, dopaminergic neurons in Mutator mice degenerated causing an L-DOPA reversible motor deficit. Other neuronal populations were unaffected. Phosphorylated ubiquitin was increased in the brains of Mutator mice, indicating PINK1-Parkin activation. Parkin loss caused mitochondrial dysfunction and affected the pathogenicity but not the levels of mtDNA somatic mutations. A systemic loss of Parkin synergizes with mitochondrial dysfunction causing dopaminergic neuron death modeling PD pathogenic processes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 07/2015; 87(2):371-381. DOI:10.1016/j.neuron.2015.06.034 · 15.05 Impact Factor
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    • "respiratory chain, suggesting that accumulation of mtDNA deletions over a certain threshold in SNpc dopaminergic neurons may cause mitochondrial functional defects associated with PD (Bender and others 2006) (Fig. 2). However, because of the circumstantial nature of data obtained from postmortem samples, it cannot be excluded that mtDNA deletions represent a secondary rather than a primary event in the pathogenesis of PD. "
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    ABSTRACT: Parkinson's disease is a common, adult-onset neurodegenerative disorder whose pathogenesis is still under intense investigation. Substantial evidence from postmortem human brain tissue, genetic- and toxin-induced animal and cellular models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of the disease. This review discusses our current understanding of Parkinson's disease-related mitochondrial dysfunction, including bioenergetic defects, mitochondrial DNA alterations, altered mitochondrial dynamics, activation of mitochondrial-dependent programmed cell death, and perturbations in mitochondrial tethering to the endoplasmic reticulum. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of neurodegeneration in Parkinson's disease. © The Author(s) 2015.
    The Neuroscientist 03/2015; DOI:10.1177/1073858415574600 · 6.84 Impact Factor
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