Intra-axonal protein synthesis in development and beyond

Author ManuscriptProteins can be locally produced in the periphery of a cell, allowing a rapid and spatially precise response to the changes in its environment. This process is especially relevant in highly polarized and morphologically complex cells such as neurons. The study of local translation in axons has evolved from being primarily focused on developing axons, to the notion that also mature axons can produce proteins. Axonal translation has been implied in several physiological and pathological conditions, and in all cases it shares common molecular actors and pathways as well as regulatory mechanisms. Here, we review the main findings in these fields, and attempt to highlight shared principles.Portuguese Foundation for Science and Technology (FCT) in the context of the FCT funded University of Minho MD/PhD Program (SFRH/BD/52322/2013). U.H. was supported by grants from the National Institutes of Health (R01MH096702), the BrightFocus Foundation, and the Irma T. Hirschl Trus

Targeting of Rough Endoplasmic Reticulum Membrane Proteins and Ribosomes in Invertebrate Neurons

The endoplasmic reticulum (ER) is divided into rough and smooth domains (RER and SER). The two domains share most proteins, but RER is enriched in some membrane proteins by an unknown mechanism. We studied RER protein targeting by expressing fluorescent protein fusions to ER membrane proteins in Caenorhabditis elegans. In several cell types RER and general ER proteins colocalized, but in neurons RER proteins were concentrated in the cell body, whereas general ER proteins were also found in neurites. Surprisingly RER membrane proteins diffused rapidly within the cell body, indicating they are not localized by immobilization. Ribosomes were also concentrated in the cell body, suggesting they may be in part responsible for targeting RER membrane proteins

Effect of methylguanidine in a model of septic shock induced by LPS

Septic shock, a severe form of sepsis, is characterized by cardiovascular collapse following microbial invasion of the body. The progressive hypotension, hyporeactivity to vasopressor agents and vascular leak leads to circulatory failure with multiple organ dysfunction and death. Many inflammatory mediators (e.g. TNF-a, IL-1 and IL-6) are involved in the pathogenesis of shock and, among them, nitric oxide (NO). The overproduction of NO during septic shock has been demonstrated to contribute to circulatory failure, myocardial dysfunction, organ injury and multiple organ failure. We have previously demonstrated with in vitro and in vivo studies that methylguanidine (MG), a guanidine compound deriving from protein catabolism, significantly inhibits iNOS activity, TNF-a release and carrageenan-induced acute inflammation in rats. The aim of the present study was to evaluate the possible anti-inflammatory activity of MG in a model of septic shock induced by lipopolysaccharide (LPS) in mice. MG was administered intraperitoneally (i.p.) at the dose of 30 mg/kg 1 h before and at 1 and 6 h after LPS-induced shock. LPS injection (10mg/kg in 0.9% NaCl; 0.1 ml/mouse; i.p.) in mouse developed a shock syndrome with enhanced NO release and liver, kidney and pancreatic damage 18 h later. NOx levels, evaluated as nitrite/nitrate serum levels, was significantly reduced in MG-treated rats (78.6%, p , 0:0001; n ¼ 10). Immunohistochemistry revealed, in the lung tissue of LPS-treated group, a positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) synthase, both of which were reduced in MG-treated mice. Furthermore, enzymatic evaluation revealed a significant reduction in liver, renal and pancreatic tissue damage andMGtreatment also improved significantly the survival rate. This study provides evidence that MG attenuates the degree of inflammation and tissue damage associated with endotoxic shock in mice. The mechanisms of the anti-inflammatory effect of MG is, at least in part, dependent on the inhibition of NO formation

Hypertonic saline resuscitation maintains a more balanced profile of T-lymphocyte subpopulations in a rat model of hemorrhagic shock

Objective: To investigate the potential and early effect of hypertonic saline resuscitation on T-lymphocyte subpopulations in rats with hemorrhagic shock. Methods: A model of rat with severe hemorrhagic shock was established in 18 Sprague-Dawley (SD) rats. The rats were randomly divided into Sham group, HTS group (hypertonic saline resuscitation group) and NS group (normal saline resuscitation group). Each group contained 6 rats. The CD4(+) and CD8(+) subpopulations of T-lymphocytes in peripheral blood were detected respectively before shock and after resuscitation by double antibody labelling and flow cytometry. Results: In the early stage after hemorrhagic shock, fluid resuscitation and emergency treatment, the CD4(+) lymphocytes of peripheral blood in HTS and NS groups markedly increased. Small volume resuscitation with HTS also induced peripheral CD8(+) lymphocytes to a certain extent, whereas NS resuscitation showed no effect in this respect. Consequently, compared with Sham and HTS groups, CD4(+)/CD8(+) ratio of peripheral blood in NS group was obviously increased, and showed statistically differences. Conclusion: In this model of rat with severe hemorrhagic shock, small volume resuscitation with HTS is more effective than NS in reducing immunologic disorders and promoting a more balanced profile of T-lymphocyte subpopulations regulating network