DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis

DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson’s disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease

Expression von TNFa und seinen Rezeptoren p55TNFR und p75TNFR im Gehirn der Maus nach SEB- und LPS-Stimulation

Zwischen Gehirn und peripherem Immunsystem besteht eine bidirektionale Kommunikation, die u.a. durch lösliche Faktoren wie Zytokine mediiert wird. Eines der dabei beteiligten Proteine ist der Tumor-Nekrose-Faktor-alpha (TNFa), ein proinflammatorisch und apoptotisch wirkendes Zytokin, das im ZNS von residenten Mikrogliazellen und Astrozyten synthetisiert werden kann. Die Voraussetzung einer Rezeptor-mediierten lokalen Wirkung des TNFa im Gehirn ist durch die nachgewiesene Expression der TNFa Rezeptoren p55TNFR und p75TNFR erfüllt. Allerdings sind die Zellentypen ebenso wie die Mechanismen, die zur Synthese der TNFa Rezeptoren führen bislang unklar. Die vorliegende Arbeit charakterisiert die zelluläre Verteilung von TNFa, p55TNFR und p75TNFR im Gehirn der Maus unter physiologischen Bedingungen und zu verschiedenen Zeitpunkten (1, 4, 8, 12 und 24h) nach intraperitonealer Injektion von Lipopolysaccharid (LPS) oder Staphylokokken Enterotoxin B (SEB). Beide Mitogene erhöhen die Serumspiegel von TNFa. Die unterschiedlichen Aktivierungsmechanismen der beiden Mitogene erlauben aber zu unterscheiden, ob Serum-TNFa alleine oder nur in Kombination mit der lokalen Wirkung eines der Mitogene direkt im ZNS zu einer Induktion der TNFa-Rezeptoren im Gehirn führt. Im unstimulierten Gehirn fand sich eine panneuronale Expression der p55TNFR mRNA, die in einzelnen Hirnnervenkernen besonders stark ausgeprägt war. Kleine, non-neuronalen Zellen im gesamten Gehirn exprimierten die p75TNFR mRNA. LPS als auch SEB führten zu einer neuronalen Aktivierung im ZNS, die sich in der Induktion von c-fos mRNA im Nucleus Paraventricularis (PVN) nachweisen ließ. Keines der beiden Mitogene beeinflusste die konstitutive Expression der p55TNFR mRNA. Dagegen führte nur die Gabe von LPS, nicht aber von SEB zu einer Erhöhung der TNFa mRNA und zu einer Induktion der p75TNFR mRNA im Bereich der Zirkumventrikulären Organe (circumventricular organs, CVOs). Aus dem Vergleich der zerebralen Reaktionen auf die periphere Gabe von SEB oder LPS lässt sich folgern, dass der afferente Schenkel der neuroimmunen Kommunikation des TNFa-Systems Mitogen-abhängig ist. Im Serum erhöhte Zytokinspiegel alleine können innerhalb der „immune-to-brain communication“ zwar Einfluss auf die neuronale Aktivität wie im PVN ausüben, sie haben aber keine modulierende Wirkung auf das TNFa-System im Gehirn

Expression von TNFa und seinen Rezeptoren p55TNFR und p75TNFR im Gehirn der Maus nach SEB- und LPS-Stimulation

Zwischen Gehirn und peripherem Immunsystem besteht eine bidirektionale Kommunikation, die u.a. durch lösliche Faktoren wie Zytokine mediiert wird. Eines der dabei beteiligten Proteine ist der Tumor-Nekrose-Faktor-alpha (TNFa), ein proinflammatorisch und apoptotisch wirkendes Zytokin, das im ZNS von residenten Mikrogliazellen und Astrozyten synthetisiert werden kann. Die Voraussetzung einer Rezeptor-mediierten lokalen Wirkung des TNFa im Gehirn ist durch die nachgewiesene Expression der TNFa Rezeptoren p55TNFR und p75TNFR erfüllt. Allerdings sind die Zellentypen ebenso wie die Mechanismen, die zur Synthese der TNFa Rezeptoren führen bislang unklar. Die vorliegende Arbeit charakterisiert die zelluläre Verteilung von TNFa, p55TNFR und p75TNFR im Gehirn der Maus unter physiologischen Bedingungen und zu verschiedenen Zeitpunkten (1, 4, 8, 12 und 24h) nach intraperitonealer Injektion von Lipopolysaccharid (LPS) oder Staphylokokken Enterotoxin B (SEB). Beide Mitogene erhöhen die Serumspiegel von TNFa. Die unterschiedlichen Aktivierungsmechanismen der beiden Mitogene erlauben aber zu unterscheiden, ob Serum-TNFa alleine oder nur in Kombination mit der lokalen Wirkung eines der Mitogene direkt im ZNS zu einer Induktion der TNFa-Rezeptoren im Gehirn führt. Im unstimulierten Gehirn fand sich eine panneuronale Expression der p55TNFR mRNA, die in einzelnen Hirnnervenkernen besonders stark ausgeprägt war. Kleine, non-neuronalen Zellen im gesamten Gehirn exprimierten die p75TNFR mRNA. LPS als auch SEB führten zu einer neuronalen Aktivierung im ZNS, die sich in der Induktion von c-fos mRNA im Nucleus Paraventricularis (PVN) nachweisen ließ. Keines der beiden Mitogene beeinflusste die konstitutive Expression der p55TNFR mRNA. Dagegen führte nur die Gabe von LPS, nicht aber von SEB zu einer Erhöhung der TNFa mRNA und zu einer Induktion der p75TNFR mRNA im Bereich der Zirkumventrikulären Organe (circumventricular organs, CVOs). Aus dem Vergleich der zerebralen Reaktionen auf die periphere Gabe von SEB oder LPS lässt sich folgern, dass der afferente Schenkel der neuroimmunen Kommunikation des TNFa-Systems Mitogen-abhängig ist. Im Serum erhöhte Zytokinspiegel alleine können innerhalb der „immune-to-brain communication“ zwar Einfluss auf die neuronale Aktivität wie im PVN ausüben, sie haben aber keine modulierende Wirkung auf das TNFa-System im Gehirn

Postural Stability in Parkinson’s Disease Patients Is Improved after Stochastic Resonance Therapy

Background. Postural instability in Parkinson’s disease (PD) increases the risk of falls and is not improved by pharmacological therapy. Objective. We performed a double-blind, randomized sham-controlled study to test the effects of stochastic resonance (whole body vibration) therapy on postural stability in PD. Methods. Fifty-six PD participants were allocated to either experimental or sham groups. The experimental group received four series of vibration over eight days, with each series consisting of six stimulus trains of 60-second duration using a randomized whole body vibration. Participants allocated to the control group received a sham treatment. Results. Within-group analysis revealed that postural stability in the experimental group improved by 17.5% (p=0.005) comparing experimental and sham groups. The between-group analysis of change after treatment comparing both groups also showed a significant improvement of postural stability (p=0.03). Only in the within-group analysis several items were improved after Bonferroni correction, too, rigor 41.6% (p=0.001), bradykinesia 23.7% (p=0.001), tremor 30.8% (p=0.006), and UPDRSIII sum score 23.9% (p=0.000), but did not reach the level of significance in the between-group analysis. Conclusions. Stochastic resonance therapy significantly enhanced postural stability even in individuals with increased risk of falling. Thus it offers a potential supplementation to canonical treatments of PD

Safety of Cerebrolysin for neurorecovery after acute ischemic stroke: a systematic review and meta-analysis of twelve randomized-controlled trials

We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis were conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p > 0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo

Epigenome-Wide Analysis of DNA Methylation in Parkinson’s Disease Cortex

Background: Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene–environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson’s disease, which that is characterised by a late onset in life. Aims: To determine epigenetic modifications in the brains of Parkinson’s disease patients. Patients and Methods: DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels of CYP2E1 were analysed using Western blot in human cortex and knock-out mice brain samples. Results: We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference >0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation of CYP2E1 was unchanged. In CYP2E1 knock-out mice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulated CYP2E1 protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes. Conclusions: Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation of CYP2E1

Epigenome-Wide Analysis of DNA Methylation in Parkinson’s Disease Cortex

Background: Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene–environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson’s disease, which that is characterised by a late onset in life. Aims: To determine epigenetic modifications in the brains of Parkinson’s disease patients. Patients and Methods: DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels of CYP2E1 were analysed using Western blot in human cortex and knock-out mice brain samples. Results: We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference >0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation of CYP2E1 was unchanged. In CYP2E1 knock-out mice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulated CYP2E1 protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes. Conclusions: Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation of CYP2E1

Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson’s disease revealed different epigenetic patterns in peripheral blood mononuclear cells

International audienceNumerous studies have elucidated the genetics of Parkinson’s disease; however, the aetiology of the majority of sporadic cases has not yet been resolved. We hypothesized that epigenetic variations could be associated with PD and evaluated the DNA methylation pattern in PD patients compared to brothers or twins without PD. The methylation of DNA from peripheral blood mononuclear cells of 62 discordant siblings including 24 monozygotic twins was characterized with Illumina DNA Methylation 450K bead arrays and subsequently validated in two independent cohorts: 221 PD vs. 227 healthy individuals (cohort 1) applying Illumina’s VeraCode and 472 PD patients vs. 487 controls (cohort 2) using pyrosequencing. We choose a delta beta of >15 % and selected 62 differentially methylated CpGs in 51 genes from the discordant siblings. Among them, three displayed multiple CpGs per gene: microRNA 886 (MIR886, 10 CpGs), phosphodiesterase 4D (PDE4D, 2 CpGs) and tripartite motif-containing 34 (TRIM34, 2 CpGs). PDE4D was confirmed in both cohorts (p value 2.44e−05). In addition, for biomarker construction, we used the penalized logistic regression model, resulting in a signature of eight CpGs with an AUC of 0.77. Our findings suggest that a distinct level of PD susceptibility stems from individual, epigenetic modifications of specific genes. We identified a signature of CpGs in blood cells that could separate control from disease with a reasonable discriminatory power, holding promise for future epigenetically based biomarker development

Psychometric Properties of an Abbreviated Version of the Apathy Evaluation Scale for Parkinson Disease (AES-12PD)

BackgroundApathy is a frequent symptom in Parkinson's disease (PD), substantially aggravating the course of PD. Regarding the accumulating evidence of the key role of apathy in PD, time-efficient assessments are useful for fostering progress in research and treatment. The Apathy Evaluation Scale (AES) is widely used for the assessment of apathy across different nosologies.ObjectiveTo facilitate the application of the AES in PD, we reduced the AES to two-thirds its length and validated this abbreviated version.DesignData sets of 339 PD patients of the DEMPARK/LANDSCAPE study without dementia and depression were randomly split into two samples. Data of sample 1 were used to develop a brief version of the AES (AES-12PD). A cross-validation was conducted in sample 2 and in a subsample of 42 PD patients with comorbid dementia and depressive symptomatology. Receiver operating characteristic analysis was applied to determine the optimal cutoff of the AES-12PD as an indicator of apathy.ResultsThe AES-12PD featured high internal consistency that was better compared to the AES. The abbreviated scale was well differentiated from motor impairment and cognitive deficits. The AES-12PD cutoff of 27/28 was the optimal cutoff for apathy in PD patients without dementia and depression. The cutoff of 25/26 indicated apathy in PD patients with comorbid dementia and depression.ConclusionResults confirm a high internal consistency and good discriminant validity of the AES-12PD. The AES-12PD represents a reliable tool for the efficient assessment of apathy that can be applied in PD patients with and without dementia and depression