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See detailMetformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Fitzgerald, Julia C.; Zimprich, Alexander; Carvajal-Berrio, Daniel A. et al

in Brain : A Journal of Neurology (2017), 140(9), 2444-2459

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 ... [more ▼]

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HtrA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HtrA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HtrA2 and PINK1. HtrA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HtrA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HtrA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies. [less ▲]

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See detailMutation analyses and association studies to assess the role of the presenilin-associated rhomboid-like gene in Parkinson's disease
Wüst, Richard; Maurer, Brigitte; Hauser, Kathrin et al

in Neurobiology of Aging (2016), 39

Presenilin-associated rhomboid-like (PARL), a serine protease located in the inner mitochondrial membrane, has been shown to genetically interact and process PTEN-induced putative kinase a protein known ... [more ▼]

Presenilin-associated rhomboid-like (PARL), a serine protease located in the inner mitochondrial membrane, has been shown to genetically interact and process PTEN-induced putative kinase a protein known for its critical role in mitochondrial homeostasis and early-onset forms of Parkinson’s disease (PD). The identification of a PD-associated variant in the PARL gene (p.Ser77Asn) led us to assess the relevance of PARL for PD pathogenesis using a mutation screening of the coding sequences and adjacent intronic sequences. We investigated 3 single nucleotide polymorphisms (rs3792589, rs13091, and rs3732581), a synonymous base substitution (Leu79Leu) and the previously described p.Ser77Asn mutation, which were subsequently screened in more than 2000 patients and controls. Not detecting the p.Ser77Asn mutation in our cohort, nor a robust association between variations in the PARL gene and PD, the role of disease causing genetic variants in the PARL gene could not be further substantiated in our samples. Our findings indicate that PARL mutations are a rare cause of PD and genetic variants are neither strong nor common risk factors in PD. [less ▲]

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See detailEffects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism.
Plewnia, Christian; Zwissler, Bastian; Langst, Isabella et al

in Cortex : A Journal Devoted to the Study of the Nervous System & Behavior (2013), 49(7), 1801-7

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a frequently used technique to investigate healthy and impaired neuronal functions. Its modulatory effect on executive functions is of ... [more ▼]

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a frequently used technique to investigate healthy and impaired neuronal functions. Its modulatory effect on executive functions is of particular interest for understanding the mechanisms underlying integration of cognition and behavior. The key role of prefrontal dopamine function for executive functions suggest that differences of the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene would interact with tDCS interventions in this domain. In this study, we hypothesized that the COMT Met allele homozygosity, associated with higher levels of prefrontal dopamine, would influence the effect of tDCS on higher-level executive functions. METHOD: Forty-six healthy subjects participated in a double-blind sham-controlled crossover study and underwent COMT genotyping. Anodal tDCS (20 min, 1 mA) to the left dorsolateral prefrontal cortex (dlPFC) or sham stimulation was applied during the performance of a parametric Go/No-Go (PGNG) test measuring sustained attention, response inhibition and cognitive flexibility as measured by set-shifting. RESULTS: In COMT Met/Met allele carrier anodal tDCS of the dlPFC was associated with a deterioration of set-shifting ability, which is assessed by the most challenging level of the PGNG. Without regard to the carrier status of the COMT Val158Met polymorphism no effects of anodal tDCS on executive functions could be determined. CONCLUSIONS: In line with the model of non-linear effects of l-dopa on cortical plasticity high dopaminergic prefrontal activity mediated by COMT Val158Met polymorphism predicts a detrimental effect of anodal tDCS on cognitive flexibility. Therefore, we suggest that the individual genetic profile may modulate behavioral effect of tDCS. More precise application of brain stimulation techniques according to the individual genetic patterns may support the development of personalized treatment approaches. [less ▲]

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See detailReduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1.
Krebiehl, Guido; Ruckerbauer, Sabine; Burbulla, Lena F. et al

in PloS one (2010), 5(2), 9367

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD ... [more ▼]

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease. [less ▲]

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