Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions

Elstner, Matthias; Müller, Sarina; Leidolt, Lars; Laub, Christoph; Krieg, Lena; Schlaudraff, Falk; Liss, Birgit; Morris, Christopher M.; Turnbull, Doug M.; Masliah, Eliezer; Prokisch, Holger; Klopstock, Thomas; Bender, Andreas

doi:10.1186/1756-6606-4-43

Cited by 45 publications

(27 citation statements)

References 43 publications

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“…From a genetic perspective, there is currently insufficient evidence to support the involvement of particular mtDNA polymorphisms with any psychiatric disorder. Despite some initial promising findings, overall it appears that mitochondrial deletions are not associated with psychiatric illness, and low level heteroplasmy for mtDNA deletions identified using LR-PCR may be attributable to aging [Elstner et al, 2011;Krishnan et al, 2011]. Similarly, two studies have failed to find significant mtDNA copy number variations in bipolar disorder, schizophrenia, and major depressive disorder.…”

Section: Summary and Future Directionsmentioning

confidence: 69%

The mitochondrial genome and psychiatric illness

Anglin

Mazurek

Tarnopolsky

et al. 2012

American J of Med Genetics Pt B

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Psychiatric disorders are a leading cause of morbidity and mortality, yet their underlying pathophysiology remains unclear. Searches for a genetic cause of bipolar disorder, schizophrenia, and major depressive disorder have yielded inconclusive results. There is increasing interest in the possibility that defects in the mitochondrial genome may play an important role in psychiatric illness. We undertook a review of the literature investigating mitochondria and adult psychiatric disorders. MEDLINE, PsycINFO, and EMBASE were searched from their inception through September 2011, and the reference lists of identified articles were reviewed for additional studies. While multiple lines of evidence, including clinical, genetic, ultrastructural, and biochemical studies, support the involvement of mitochondria in the pathophysiology of psychiatric illness, many studies have methodological limitations and their findings have not been replicated. Clinical studies suggest that psychiatric features can be prominent, and the presenting features of mitochondrial disorders. There is limited but inconsistent evidence for the involvement of mitochondrial DNA haplogroups and mitochondria-related nuclear gene polymorphisms, and for mitochondrial ultrastructural and biochemical abnormalities in psychiatric illness. The current literature suggests that mitochondrial dysfunction and mitochondrial genetic variations may play an important role in psychiatric disorders, but additional methodologically rigorous and adequately powered studies are needed before definitive conclusions can be drawn.

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Section: Summary and Future Directionsmentioning

confidence: 69%

The mitochondrial genome and psychiatric illness

Anglin

Mazurek

Tarnopolsky

et al. 2012

American J of Med Genetics Pt B

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“…However, mutations may arise independently of damaged DNA through other mechanisms, and therefore mutational analysis is not necessarily an indirect measure of oxidative DNA damage. Levels of somatic mitochondrial DNA (mtDNA) mutations are modestly increased in late-stage PD patients [46–48]. Interestingly, larger increases in mtDNA mutations are reported in incidental LB disease (presumed to be pre-symptomatic PD) compared to late-stage PD or controls [49].…”

Section: Oxidative Damage In Human Pdmentioning

confidence: 99%

Oxidative damage to macromolecules in human Parkinson disease and the rotenone model

Sanders

Greenamyre

2013

Free Radical Biology and Medicine

293

204

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Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is associated with selective degeneration of nigrostriatal dopamine neurons. While the underlying mechanisms contributing to neurodegeneration in PD appear to be multifactorial, mitochondrial impairment and oxidative stress are widely considered to be central to many forms of the disease. Whether oxidative stress is a cause or consequence of dopaminergic death, there is substantial evidence for oxidative stress in both human PD patients and in animal models of PD, especially using rotenone, a complex I inhibitor. There are many indices of oxidative stress, but this review covers the recent evidence for oxidative damage to nucleic acids, lipids and proteins in both the brain and peripheral tissues in human PD and in the rotenone model. Limitations of the existing literature and future perspectives are discussed. Understanding how each particular macromolecule is damaged by oxidative stress and the interplay of secondary damage to other biomolecules may help design better targets for treatment of PD.

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“…DNA damage is distinct from DNA mutations, which are changes in the base sequence of the DNA. Higher levels of mitochondrial mutations have been found in dopaminergic neurons in the substantia nigra of PD patients relative to healthy controls and this has raised speculation for a causal relationship between mutations and neurodegeneration (10-12). However, methodological questions remain about the analysis of variations in mitochondrial DNA sequence and its functional significance (13).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA damage: Molecular marker of vulnerable nigral neurons in Parkinson's disease

Sanders

McCoy

et al. 2014

Neurobiology of Disease

165

139

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DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the role of mitochondrial DNA (mtDNA) damage in human postmortem brain tissue and in in vivo and in vitro models of PD, using a newly adapted histochemical assay for abasic sites and a quantitative polymerase chain reaction (QPCR)-based assay. We identified the molecular identity of mtDNA damage to be apurinic/apyrimidinic (abasic) sites in substantia nigra dopamine neurons, but not in cortical neurons from postmortem PD specimens. To model the systemic mitochondrial impairment of PD, rats were exposed to the pesticide rotenone. After rotenone treatment that does not cause neurodegeneration, abasic sites were visualized in nigral neurons, but not in cortex. Using a QPCR-based assay, a single rotenone dose induced mtDNA damage in midbrain neurons, but not in cortical neurons; similar results were obtained in vitro in cultured neurons. Importantly, these results indicate that mtDNA damage is detectable prior to any signs of degeneration – and is produced selectively in midbrain neurons under conditions of mitochondrial impairment. The selective vulnerability of midbrain neurons to mtDNA damage was not due to differential effects of rotenone on complex I since rotenone suppressed respiration equally in midbrain and cortical neurons. However, in response to complex I inhibition, midbrain neurons produced more mitochondrial H2O2 than cortical neurons. We report selective mtDNA damage as a molecular marker of vulnerable nigral neurons in PD and suggest that this may result from intrinsic differences in how these neurons respond to complex I defects. Further, the persistence of abasic sites suggests an ineffective base excision repair response in PD.

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Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions

Cited by 45 publications

References 43 publications

The mitochondrial genome and psychiatric illness

The mitochondrial genome and psychiatric illness

Oxidative damage to macromolecules in human Parkinson disease and the rotenone model

Mitochondrial DNA damage: Molecular marker of vulnerable nigral neurons in Parkinson's disease

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