Investigating the immunoreactivity of inhibitors of axonal regeneration in an animal model of amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis is a devastating neurodegenerative disease that affects motor neurons. Many theories about mechanisms contributing in its pathogenesis have been suggested. There is also evidence for alterations in synaptic plasticity during the progress of ALS. In particular, the expression of axonal growth promoting molecules like GAP-43, responsible for axonal regeneration, have been suggested to be sustained during the disease. On the other hand, axonal inhibitory molecules like Nogo-A seem to play an important part in compensating this regeneration attempt. In order to investigate the role of these two participating proteins during the preclinical and clinical stages of ALS, the spinal cord of SOD1 mice, the animal model mimicking one genetic form of ALS, have been examined. Using immunocytochemistry, immunoreactivity of Nogo-A and GAP-43 was shown in spinal cord sections of 6, 13 and 18 weeks of age. Our results suggest that Nogo-A has increased irnrnunoreactivity in the oligodentrocytes in the ventral horns in grey matter of the spinal cord of the clinical Tg SOD1 mice and in the ventral white matter during preclinical and clinical stages. Increased immunoreatcivity was also found in the ventral horn neurons of the 13 weeks Tg mice compared to the other stages. GAP-43 has also shown greater immunoreactivity in Tg mice relating to the controls. These results suggest that a regeneration attempt is likely to happen during ALS but is maybe compensated by the inhibition of axonal growth at the later stages

A study of selective vulnerability to diabetes of nerves supplying the ileum using in vitro models

Autonomic neuropathy is a complication of diabetes and, where the innervation of the gut is involved, results in disordered gut motility. In vivo, sympathetic nerves and subpopulations of enteric neurons supplying the ileum are differentially affected by diabetes. The overall of aim of this study was to establish whether such differential susceptibility could be reproduced in vitro using wholemount preparations of myenteric plexus and sympathetic ganglion explants from the adult rat and to use such models to examine potential mechanisms underlying the development of neuropathy and its prevention. Preparations were exposed to a range of stimuli that mimic the diabetic environment including high glucose, advanced glycation endproducts (AGEs), carbonyl stress and oxidative stress. Evidence is presented that exposure of myenteric neurons to oxidative stress in vitro mimicked the effects of diabetes as reflected by increased expression of vasoactive intestinal polypeptide (VIP), decreased expression of neuronal nitric oxide synthase (nNOS) and unaltered calbindin expression. However, the mechanism underlying oxidative stress was not uniform, increased VIP expression only occurred on exposure to high glucose and carbonyl stress whereas decreased nNOS expression was only induced by AGEs. Neurons containing calbindin were resistant to all stimuli. Potential therapeutic agents produced differing effects depending on whether they primarily acted against oxidative or carbonyl stress. Using two photon microscopy and fluorescence lifetime imaging (FLIM), the effect of high glucose on reduced nicotinamide adenine (phosphate) (NAD(P)H) metabolism was investigated over time. Comparisons were made between sympathetic neurons from superior cervical ganglia (SCG), which are unaffected in diabetes, and from superior mesenteric/coeliac ganglia (CG/SMG) which develop axonal dystrophy. High glucose temporarily increased NAD(P)H levels selectively in the CG/SMG which coincided with a significant difference between the two ganglia in the fluorescence lifetime of free NAD(P)H. These results may explain the complex pattern of change that occurs in enteric nerves in diabetes

Understanding the evolution of immune genes in jawed vertebrates

Driven by co-evolution with pathogens, host immunity continuously adapts to optimize defence against pathogens within a given environment. Recent advances in genetics, genomics and transcriptomics have enabled a more detailed investigation into how immunogenetic variation shapes the diversity of immune responses seen across domestic and wild animal species. However, a deeper understanding of the diverse molecular mechanisms that shape immunity within and among species is still needed to gain insight into-and generate evolutionary hypotheses on-the ultimate drivers of immunological differences. Here, we discuss current advances in our understanding of molecular evolution underpinning jawed vertebrate immunity. First, we introduce the immunome concept, a framework for characterizing genes involved in immune defence from a comparative perspective, then we outline how immune genes of interest can be identified. Second, we focus on how different selection modes are observed acting across groups of immune genes and propose hypotheses to explain these differences. We then provide an overview of the approaches used so far to study the evolutionary heterogeneity of immune genes on macro and microevolutionary scales. Finally, we discuss some of the current evidence as to how specific pathogens affect the evolution of different groups of immune genes. This review results from the collective discussion on the current key challenges in evolutionary immunology conducted at the ESEB 2021 Online Satellite Symposium: Molecular evolution of the vertebrate immune system, from the lab to natural populations

Understanding the evolution of immune genes in jawed vertebrates.

Driven by co-evolution with pathogens, host immunity continuously adapts to optimize defence against pathogens within a given environment. Recent advances in genetics, genomics and transcriptomics have enabled a more detailed investigation into how immunogenetic variation shapes the diversity of immune responses seen across domestic and wild animal species. However, a deeper understanding of the diverse molecular mechanisms that shape immunity within and among species is still needed to gain insight into-and generate evolutionary hypotheses on-the ultimate drivers of immunological differences. Here, we discuss current advances in our understanding of molecular evolution underpinning jawed vertebrate immunity. First, we introduce the immunome concept, a framework for characterizing genes involved in immune defence from a comparative perspective, then we outline how immune genes of interest can be identified. Second, we focus on how different selection modes are observed acting across groups of immune genes and propose hypotheses to explain these differences. We then provide an overview of the approaches used so far to study the evolutionary heterogeneity of immune genes on macro and microevolutionary scales. Finally, we discuss some of the current evidence as to how specific pathogens affect the evolution of different groups of immune genes. This review results from the collective discussion on the current key challenges in evolutionary immunology conducted at the ESEB 2021 Online Satellite Symposium: Molecular evolution of the vertebrate immune system, from the lab to natural populations