ER stress inhibits neuronal death by promoting autophagy

Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases but its relationship and role in disease progression remain unclear. Using genetic and pharmacological approaches, we showed that mild ER stress ("preconditioning") is neuroprotective in Drosophila and mouse models of Parkinson disease. In addition, we found that the combination of mild ER stress and apoptotic signals triggers an autophagic response both in vivo and in vitro. We showed that when autophagy is impaired, ER-mediated protection is lost. We further demonstrated that autophagy inhibits caspase activation and apoptosis. Based on our findings, we conclude that autophagy is required for the neuroprotection mediated by mild ER stress, and therefore ER preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.     

Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used Ercc1 mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged Ercc1 mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and Ercc1 mutant hippocampal neurons displayed normal outgrowth and synapse formation in vitro. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline.     

GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation

Background

After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARβ/δ with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl₄) treatment in mice. Wild type and PPARβ/δ-null mice were treated with CCl₄ alone or CCl₄ co-administered with GW501516. To unveil mechanisms underlying the PPARβ/δ-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARβ/δ.

Results

We found that GW501516 treatment enhanced the fibrotic response. Compared to the other experimental groups, CCl₄/GW501516-treated wild type mice exhibited increased expression of various profibrotic and pro-inflammatory genes, such as those involved in extracellular matrix deposition and macrophage recruitment. Importantly, compared to healthy liver, hepatic fibrotic tissues from alcoholic patients showed increased expression of several PPAR target genes, including phosphoinositide-dependent kinase-1, transforming growth factor beta-1, and monocyte chemoattractant protein-1. GW501516 stimulated HSC proliferation that caused enhanced fibrotic and inflammatory responses, by increasing the phosphorylation of p38 and c-Jun N-terminal kinases through the phosphoinositide-3 kinase/protein kinase-C alpha/beta mixed lineage kinase-3 pathway.

Conclusions

This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.     

Evolutionary and Biological Implications of Dental Mesial Drift in Rodents: The Case of the Ctenodactylidae (Rodentia,Mammalia)

Dental characters are importantly used for reconstructing the evolutionary history of mammals, because teeth represent the most abundant material available for the fossil species. However, the characteristics of dental renewal are presently poorly used, probably because dental formulae are frequently not properly established, whereas they could be of high interest for evolutionary and developmental issues. One of the oldest rodent families, the Ctenodactylidae, is intriguing in having longstanding disputed dental formulae. Here, we investigated 70 skulls among all extant ctenodactylid genera (Ctenodactylus, Felovia, Massoutiera and Pectinator) by using X-ray conventional and synchrotron microtomography in order to solve and discuss these dental issues. Our study clearly indicates that Massoutiera, Felovia and Ctenodactylus differ from Pectinator not only by a more derived dentition, but also by a more derived eruptive sequence. In addition to molars, their dentition only includes the fourth deciduous premolars, and no longer bears permanent premolars, conversely to Pectinator. Moreover, we found that these premolars are lost during adulthood, because of mesial drift of molars. Mesial drift is a striking mechanism involving migration of teeth allowed by both bone remodeling and dental resorption. This dental innovation is to date poorly known in rodents, since it is only the second report described. Interestingly, we noted that dental drift in rodents is always associated with high-crowned teeth favoring molar size enlargement. It can thus represent another adaptation to withstand high wear, inasmuch as these rodents inhabit desert environments where dust is abundant. A more accurate study of mesial drift in rodents would be very promising from evolutionary, biological and orthodontic points of view.     

A role for PP1/NIPP1 in steering migration of human cancer cells

Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1) and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1-dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells.     

Ezrin ubiquitylation by the E3 ubiquitin ligase, WWP1, and consequent regulation of hepatocyte growth factor receptor activity

The membrane cytoskeleton linker ezrin participates in several functions downstream of the receptor Met in response to Hepatocyte Growth Factor (HGF) stimulation. Here we report a novel interaction of ezrin with a HECT E3 ubiquitin ligase, WWP1/Aip5/Tiul1, a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancers. We show that ezrin binds to the WW domains of WWP1 via the consensus motif PPVY(477) present in ezrin's C-terminus. This association results in the ubiquitylation of ezrin, a process that requires an intact PPVY(477) motif. Interestingly ezrin ubiquitylation does not target the protein for degradation by the proteasome. We find that ezrin ubiquitylation by WWP1 in epithelial cells leads to the upregulation of Met level in absence of HGF stimulation and increases the response of Met to HGF stimulation as measured by the ability of the cells to heal a wound. Interestingly this effect requires ubiquitylated ezrin since it can be rescued, after depletion of endogenous ezrin, by wild type ezrin but not by a mutant of ezrin that cannot be ubiquitylated. Taken together our data reveal a new role for ezrin in Met receptor stability and activity through its association with the E3 ubiquitin ligase WWP1. Given the role of Met in cell proliferation and tumorigenesis, our results may provide a mechanistic basis for understanding the role of ezrin in tumor progression.     

School absenteeism as an adjunct surveillance indicator: experience during the second wave of the 2009 H1N1 pandemic in Quebec, Canada

Background

A school absenteeism surveillance system was implemented in the province of Quebec, Canada during the second wave of the 2009 H1N1pandemic. This paper compares this surveillance approach with other available indicators.

Method

All (3432) elementary and high schools from Quebec were included. Each school was required to report through a web-based system any day where the proportion of students absent for influenza-like illness (ILI) exceeded 10% of current school enrolment.

Results

Between October 18 and December 12 2009, 35.6% of all schools met the 10% absenteeism threshold. This proportion was greater in elementary compared to high schools (40% vs 19%) and in smaller compared to larger schools (44% vs 22%). The maximum absenteeism rate was reached the first day of reporting or within the next two days in 55% and 31% of schools respectively. The first reports and subsequent peak in school absenteeism provincially preceded the peak in paediatric hospitalization by two and one weeks, respectively. Trends in school surveillance otherwise mirrored other indicators.

Conclusion

During a pandemic, school outbreak surveillance based on a 10% threshold appears insufficient to trigger timely intervention within a given affected school. However, school surveillance appears well-correlated and slightly anticipatory compared to other population indicators. As such, school absenteeism warrants further evaluation as an adjunct surveillance indicator whose overall utility will depend upon specified objectives, and other existing capacity for monitoring and response.