Exosomal cell-to-cell transmission of alpha synuclein oligomers

Background

Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC) disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i) NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF) after axotomy and ii) PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF.

Results

NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT), whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-?? signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A.

Conclusions

Our results suggest that the NPC cellular phenotype causes neuronal dysfunction through the abnormal up-regulation of survival pathways, which causes the perturbation of signaling cascades and anomalous phosphorylation of the cytoskeleton.     

Kainic acid-induced changes in the opioid/nociceptin system and the stress/toxicity pathways in the rat hippocampus

Excitotoxicity is a contributing factor to the pathogenesis of acute or chronic neurodegenerative disease states. Kainic acid (KA) is an excitotoxic substance and the administration of it to rodents induces seizure activity (status epilepticus, SE) and leads to neurodegeneration. In this study the effect of KA-induced excitotoxicity on the G-protein activations and the gene expression levels of the opioid/nociceptin system receptors as MOPr, KOPr, DOPr, ORL-1, and PNOC (N/OFQ) were investigated, and the regulator effect of naloxone (Nal) on the gene expressions of the opioid system receptors against KA-induced seizures in the rat hippocampus was tested. In addition, the expression levels of stress-toxicity genes were assessed in the hippocampus following KA-induced excitotoxicity in order to determine the potential genetic targets which can be helpful for neuroprotective interventions. Our results indicate that the KA-induced excitotoxicity increased the mRNA levels of MOPr, DOPr, KOPr, PNOC, and ORL-1. However, G-protein activations of MOPr, DOPr, and KOPr remained relatively unchanged while both the potency and efficacy of N/OFQ were significantly increased. The PCR array data showed that KA-induced excitotoxicity altered the expression levels of genes in the cellular stress or toxicity pathways. Our data suggests that the induction of the opioid/nociceptin system may be involved in the cellular stress response following a neurodegenerative insult and that the genes modulated by the KA-treatment in the stress-toxicity pathways may be evaluated as targets of potential neuroprotective interventions.     

Protective effect of selenium against mercury-induced toxicity on hematological and biochemical parameters of Oreochromis niloticus

In this study, to identify mercury (Hg) toxicity and whether selenium (Se) has any role in alleviation of this toxicity, it was investigated the changes in hematological and serum biochemical parameters of Oreochromis niloticus. Fish were exposed to 0.01 and 0.1 mg/L Hg and 0.01 mg/L Hg + 0.1 mg/L Se and 0.1 mg/L Hg + 1.0 mg/L Se for 7 and 14 days. The exposure of O. niloticus to Hg alone resulted in decreases in red blood cell, white blood cell, hemoglobin, hematocrit values, and cholinesterase activity while it increased in alanine aminotransferase and aspartate aminotransferase activities and cortisol and glucose levels. Se, in combination with Hg, partially or totally caused an alleviation for the toxic effect of Hg on the above mentioned hematological and biochemical parameters. The results of our study showed that Se has a protective effect against toxicity induced by Hg.     

PCR-based methods for identification of Enterococcus species

Two DNA-based techniques were used for species identification of enterococci.PvuII digestion of the genus-specific PCR product yielded four different restriction profiles among 20 enterococcal species; one of them was species-specific forE. faecium. In the second case, 32 reference strains belonging to 20 enterococcal species were divided to 12 groups by amplification of internal transcribed spacer of rRNA operon. Interspecies and some intraspecies profile variability was determined. Both methods gave similar results.     

Cerebral palsy due to nonlethal maternal carbon monoxide intoxication

BACKGROUND: Carbon monoxide (CO) poisoning in pregnancy is a relatively rare occurrence, but it can result in fetal mortality and neurologic complications in fetuses who survive to term. CASE: We describe the course of an infant who was acutely exposed to CO at 20 weeks of gestation. CONCLUSIONS: We conclude that despite maternal well-being, CO intoxication at critical periods of human brain development can lead to hypoxic-ischemic lesions in the globus pallidus and that dystonic cerebral palsy may develop in the infant during long-term follow-up.     

A GID E3 ligase assembly ubiquitinates an Rsp5 E3 adaptor and regulates plasma membrane transporters

Cells rapidly remodel their proteomes to align their cellular metabolism to environmental conditions. Ubiquitin E3 ligases enable this response, by facilitating rapid and reversible changes to protein stability, localization, or interaction partners. In Saccharomyces cerevisiae, the GID E3 ligase regulates the switch from gluconeogenic to glycolytic conditions through induction and incorporation of the substrate receptor subunit Gid4, which promotes the degradation of gluconeogenic enzymes. Here, we show an alternative substrate receptor, Gid10, which is induced in response to changes in temperature, osmolarity, and nutrient availability, regulates the ART‐Rsp5 ubiquitin ligase pathway, a component of plasma membrane quality control. Proteomic studies reveal that the levels of the adaptor protein Art2 are elevated upon GID10 deletion. A crystal structure shows the basis for Gid10‐Art2 interactions, and we demonstrate that Gid10 directs a GID E3 ligase complex to ubiquitinate Art2. Our data suggest that the GID E3 ligase affects Art2‐dependent amino acid transport. This study reveals GID as a system of E3 ligases with metabolic regulatory functions outside of glycolysis and gluconeogenesis, controlled by distinct stress‐specific substrate receptors.     

Effect of various nerve decompression procedures on the functions of distal limbs in streptozotocin-induced diabetic rats: further optimism in diabetic neuropathy

It is known that diabetic neuropathy is the result of endoneurial edema caused by various biochemical reactions triggered by hyperglycemia. This sequence of events can cause cessation of circulation at the perineurial level, or the tough layer, which is not resilient enough to spread intraneural pressure. Internal and external limiting structures create a double crush phenomenon to the nerve structure. Decompression of the nerve trunk at separate levels is one of the adjuncts to the overall treatment plan for diabetic neuropathy. In this study, the right sciatic nerves of 30 rats with streptozotocin-induced diabetes were used; three groups were created. In the control group, the sciatic nerves were explored and dissected only. In group II, tarsal tunnel release was performed and accompanied by epineurotomy of the sciatic nerve and its peroneal and tibial extensions. In group III, in addition to the procedures performed in group II, perineural sheaths, exposed through the epineurotomy sites at both the peroneal and tibial nerves, were incised for decompression of the fascicles. Improvement in diabetic neuropathy was evaluated by using footprint parameters. The last print length values, estimated according to the 38-month measurements, were 26.1 +/- 0.12 mm in the control group, 23.2 +/- 0.07 mm in group II, and 22.2 +/- 0.1 mm in group III. The toe spread and intermediate toe spread values of the groups were parallel to improvements in print lengths throughout the study. The best improvement was observed in the perineurotomy group. Finally, an electron microscopic study revealed variable degenerative changes in all groups, but they were milder in groups II and III. This experimental study reveals that adding internal decompression to external release doubled the effect in reducing derangement in the sciatic nerves of the rats and, in the authors' opinion, offers cause for further optimism in the treatment of diabetic neuropathy.     

Achene anatomy and stomatal characteristics of eighteen Crepis L. (Asteraceae) taxa from Turkey with notes on their systematic significance

Achene anatomy and stomatal characteristics of eighteen Crepis taxa from Turkey are here described for the first time. In all taxa examined the pericarp is composed of several layers of sclerenchymatous and parenchymatous cells. As for the achene, differences among taxa mainly concern the pericarp structure and its thickness and width. Stomata are present on both surface of the leaf in all studied taxa and all taxa have anomocytic type stomata. However, the dimensions (length and width) and density of the stomata differ significantly among the studied taxa. In addition, the dimensions of stomata are negatively correlated with stomata density. It is concluded that achene anatomy and stomatal characteristics are useful for delimitation of Crepis taxa and a key to taxa based on these characters is provided. However, based on achene anatomy and stomatal characteristics, we found no argument for an exclusion of the Lagoseris group from Crepis as has previously been proposed.