α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel,Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease

Participation of the small, intrinsically disordered protein α-synuclein (α-syn) in Parkinson disease (PD) pathogenesis has been well documented. Although recent research demonstrates the involvement of α-syn in mitochondrial dysfunction in neurodegeneration and suggests direct interaction of α-syn with mitochondria, the molecular mechanism(s) of α-syn toxicity and its effect on neuronal mitochondria remain vague. Here we report that at nanomolar concentrations, α-syn reversibly blocks the voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane that controls most of the metabolite fluxes in and out of the mitochondria. Detailed analysis of the blockage kinetics of VDAC reconstituted into planar lipid membranes suggests that α-syn is able to translocate through the channel and thus target complexes of the mitochondrial respiratory chain in the inner mitochondrial membrane. Supporting our in vitro experiments, a yeast model of PD shows that α-syn toxicity in yeast depends on VDAC. The functional interactions between VDAC and α-syn, revealed by the present study, point toward the long sought after physiological and pathophysiological roles for monomeric α-syn in PD and in other α-synucleinopathies.     

Allergic airway inflammation induces the migration of dendritic cells into airway sensory ganglia

Background

A neuroimmune crosstalk between dendritic cells (DCs) and airway nerves in the lung has recently been reported. However, the presence of DCs in airway sensory ganglia under normal and allergic conditions has not been explored so far. Therefore, this study aims to investigate the localisation, distribution and proliferation of DCs in airway sensory ganglia under allergic airway inflammation.

Methods

Using the house dust mite (HDM) model for allergic airway inflammation BALB/c mice were exposed to HDM extract intranasally (25 μg/50 μl) for 5 consecutive days a week over 7 weeks. With the help of the immunohistochemistry, vagal jugular-nodose ganglia complex (JNC) sections were analysed regarding their expression of DC-markers (MHC II, CD11c, CD103), the neuronal marker PGP 9.5 and the neuropeptide calcitonin gene-related peptide (CGRP) and glutamine synthetase (GS) as a marker for satellite glia cells (SGCs). To address the original source of DCs in sensory ganglia, a proliferation experiment was also carried in this study.

Results

Immune cells with characteristic DC-phenotype were found to be closely located to SGCs and vagal sensory neurons under physiological conditions. The percentage of DCs in relation to neurons was significantly increased by allergic airway inflammation in comparison to the controls (HDM 51.38 ± 2.38% vs. control 28.16 ± 2.86%, p < 0.001). The present study also demonstrated that DCs were shown to proliferate in jugular-nodose ganglia, however, the proliferation rate of DCs is not significantly changed in the two treated animal groups (proliferating DCs/ total DCs: HDM 0.89 ± 0.38%, vs. control 1.19 ± 0.54%, p = 0.68). Also, increased number of CGRP-positive neurons was found in JNC after allergic sensitisation and challenge (HDM 31.16 ± 5.41% vs. control 7.16 ± 1.53%, p < 0.001).

Conclusion

The present findings suggest that DCs may migrate from outside into the ganglia to interact with sensory neurons enhancing or protecting the allergic airway inflammation. The increase of DCs as well as CGRP-positive neurons in airway ganglia by allergic airway inflammation indicate that intraganglionic DCs and neurons expressing CGRP may contribute to the pathogenesis of bronchial asthma. To understand this neuroimmune interaction in allergic airway inflammation further functional experiments should be carried out in future studies.     

A Critical Review of the Arsenic Uptake Mechanisms and Phytoremediation Potential of Pteris vittata

The discovery of the arsenic hyperaccumulator, Pteris vittata (Chinese brake fern), has contributed to the promotion of its application as a means of phytoremediation for arsenic removal from contaminated soils and water. Understanding the mechanisms involved in arsenic tolerance and accumulation of this plant provides valuable tools to improve the phytoremediation efficiency. In this review, the current knowledge about the physiological and molecular mechanisms of arsenic tolerance and accumulation in P. vittata is summarized, and an attempt has been made to clarify some of the unresolved questions related to these mechanisms. In addition, the capacity of P. vittata for remediation of arsenic-contaminated soils is evaluated under field conditions for the first time, and possible solutions to improve the remediation capacity of Pteris vittata are also discussed.     

Evolutionary Phylodynamics of Korean Noroviruses Reveals a Novel GII.2/GII.10 Recombination Event

Viral gastroenteritis is the most common causal agent of public health problems worldwide. Noroviruses cause nonbacterial acute gastroenteritis in humans of all ages. In this study, we investigated the occurrence of norovirus infection in children with acute gastroenteritis admitted to university hospitals in South Korea. We also analyzed the genetic diversity of the viruses and identified novel recombination events among the identified viral strains. Of 502 children with acute gastroenteritis admitted to our three hospitals between January 2011 and March 2012, genotyping of human noroviruses was performed in 171 (34%) norovirus-positive samples. Of these samples, 170 (99.5%) were in genogroup II (GII), while only one (0.5%) was in genogroup I (GI). The most common GII strain was the GII.4-2006b variant (n = 96, 56.5%), followed by GII.6 (n = 23, 13.5%), GII.12 (n = 22, 12.9%), GII.3 (n = 20, 11.8%), GII.2 (n = 6, 3.5%), GII.b (n = 2, 1.2%), and GII.10 (n = 1, 0.6%). Potential recombination events (polymerase/capsid) were detected in 39 GII strains (22.9%), and the most frequent genotypes were GII.4/GII.12 (n = 12, 30.8%), GII.4/GII.6 (n = 12, 30.8%), GII.4/GII.3 (n = 8, 20.5%), GII.b/GII.3 (n = 3, 7.7%), GII.16/GII.2 (n = 2, 5.1%), GII.4/GII.2 (n = 1, 2.6%), and GII.2/GII.10 (n = 1, 2.6%). For the first time, a novel GII.2/GII.10 recombination was detected; we also identified the GII.16/GII.2 strain for the first time in South Korea. Our data provided important insights into new recombination events, which may prove valuable for predicting the emergence of circulating norovirus strains with global epidemic potential.     

Omeprazole Blocks STAT6 Binding to the Eotaxin-3 Promoter in Eosinophilic Esophagitis Cells

Background

Patients who have esophageal eosinophilia without gastroesophageal reflux disease (GERD) nevertheless can respond to proton pump inhibitors (PPIs), which can have anti-inflammatory actions independent of effects on gastric acid secretion. In esophageal cell cultures, omeprazole has been reported to inhibit Th2 cytokine-stimulated expression of eotaxin-3, an eosinophil chemoattractant contributing to esophageal eosinophilia in eosinophilic esophagitis (EoE). The objective of this study was to elucidate molecular mechanisms underlying PPI inhibition of IL-4-stimulated eotaxin-3 production by esophageal cells.

Methods/Findings

Telomerase-immortalized and primary cultures of esophageal squamous cells from EoE patients were treated with IL-4 in the presence or absence of acid-activated omeprazole or lansoprazole. We measured eotaxin-3 protein secretion by ELISA, mRNA expression by PCR, STAT6 phosphorylation and nuclear translocation by Western blotting, eotaxin-3 promoter activation by an exogenous reporter construct, and STAT6, RNA polymerase II, and trimethylated H3K4 binding to the endogenous eotaxin-3 promoter by ChIP assay. Omeprazole in concentrations ≥5 µM significantly decreased IL-4-stimulated eotaxin-3 protein secretion and mRNA expression. Lansoprazole also blocked eotaxin-3 protein secretion. Omeprazole had no effect on eotaxin-3 mRNA stability or on STAT6 phosphorylation and STAT6 nuclear translocation. Rather, omeprazole blocked binding of IL-4-stimulated STAT6, RNA polymerase II, and trimethylated H3K4 to the eotaxin-3 promoter.

Conclusions/Significance

PPIs, in concentrations achieved in blood with conventional dosing, significantly inhibit IL-4-stimulated eotaxin-3 expression in EoE esophageal cells and block STAT6 binding to the promoter. These findings elucidate molecular mechanisms whereby patients with Th2 cytokine-driven esophageal eosinophilia can respond to PPIs, independent of effects on gastric acid secretion.