We have investigated the role of the Eph family of receptor tyrosine kinases and their ligands in the establishment of the vomeronasal projection in the mouse. Our data show intriguing differential ...expression patterns of ephrin-A5 on vomeronasal axons and of EphA6 in the accessory olfactory bulb (AOB), such that axons with high ligand concentration project onto regions of the AOB with high receptor concentration and vice versa. These data suggest a mechanism for development of this projection that is the opposite of the repellent interaction between Eph receptors and ligands observed in other systems. In support of this idea, when given the choice of whether to grow on lanes containing EphA-F(c)/laminin or F(c)/laminin protein (in the stripe assay), vomeronasal axons prefer to grow on EphA-F(c)/laminin. Analysis of ephrin-A5 mutant mice revealed a disturbance of the topographic targeting of vomeronasal axons to the AOB. In summary, these data, which are derived from in vitro and in vivo experiments, indicate an important role of the EphA family in setting up the vomeronasal projection.
Abstract The supplementation of creatine (Cr) has a marked neuroprotective effect in mouse models of neurodegenerative diseases. This has been assigned to the known bioenergetic, anti-apoptotic, ...anti-excitotoxic, and anti-oxidant properties of Cr. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral Cr supplementation on aging in 162 aged C57Bl/6J mice. Outcome variables included “healthy” life span, neurobehavioral phenotyping, as well as morphology, biochemistry, and expression profiling from brain. The median healthy life span of Cr-fed mice was 9% higher than in control mice, and they performed significantly better in neurobehavioral tests. In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the “aging pigment” lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging.
Highlights • Otx2 overexpression results in an increased number of midbrain dopaminergic DA neurons. • Otx2-overexpressing mice show increased dopamine transporter expression and hypolocomotion. • ...Otx2-overexpressing mice show an increased number of parvalbumin-positive cells and a peculiar c- fos mRNA after KA seizures.
Lifetime Study in mice: radiation‐induced cataract Dalke, C.; Kunze, S.; Rößler, U. ...
Acta ophthalmologica (Oxford, England),
September 2017, 2017-09-00, 20170901, Letnik:
95, Številka:
S259
Journal Article
Recenzirano
Odprti dostop
Summary
We did a lifetime study in irradiated and control mice with a follow up time until 24 months post irradiation with repeated in vivo analysis of the lens density and the retina.
Mice of ...different genetic constitution (wild‐type, Ercc2+/‐) were acutely whole body irradiated with low doses of ionising radiation (0, 63, 125 and 500 mGy) and a low dose rate (63 mGy/min). Lens opacification was analysed monthly by Scheimpflug imaging and the retinal fundus and thickness was analysed by OCT. At different time points (4 and 24 hours, 12, 18 and 24 months post irradiation) mice were sacrificed and eyes were analysed by histology and immunohistochemistry.
Mice of all groups, even the DNA repair helicase deficient mice (Ercc2+/−), did not develop clinically relevant radiation‐dependent lens opacities. Only an age‐dependent increase of lens density was identified. Consequently, no major morphological changes were visible in the eye histology of all mice. Immunohistochemical staining against DNaseIIb revealed no differences between the groups as well as 8‐OHG staining resulted in similar ROS levels in all irradiation groups. However, non‐irradiated Ercc2+/‐ mice showed an increased level of oxidative stress compared to wild‐type mice.
We report on the development of a novel assay protocol for the separation and detection of charge isoforms of DJ-1 in biological samples by automated capillary isoelectric focusing followed by ...immunological detection. DJ-1 (PARK7) is considered as a biomarker candidate for Parkinson’s disease and may potentially support the differentiation of clinical subtypes of the disease. The new method allows for separation and subsequent relative quantitative comparison of different isoforms of DJ-1 in biological samples. The assay was successfully applied to the analysis of DJ-1 isoform patterns in brains from mice subjected to normal or high-fat diet and revealed statistically significant group differences. Furthermore, in a pooled and concentrated sample of human cerebrospinal fluid that was depleted of albumin and immunoglobulin G, four different charge variants of DJ-1 could be detected. Taken together, the capillary isoelectric focusing immunoassay for DJ-1 represents a promising tool that may ultimately serve in clinical biomarker studies.
Loss of function of DJ‐1 (PARK7) is associated with autosomal recessive early‐onset Parkinson's disease (PD), one of the major age‐related neurological diseases. In this study, we extended former ...studies on DJ‐1 knockout mice by identifying subtle morphological and behavioural phenotypes. The DJ‐1 gene trap‐induced null mutants exhibit less dopamine‐producing neurons in the ventral tegmental area (VTA). They also exhibit slight changes in behaviour, i.e. diminished rearing behaviour and impairments in object recognition. Furthermore, we detected subtle phenotypes, which suggest that these animals compensate for the loss of DJ‐1. First, we found a significant upregulation of mitochondrial respiratory enzyme activities, a mechanism known to protect against oxidative stress. Second, a close to significant increase in c‐Jun N‐terminal kinase 1 phosphorylation in old DJ‐1‐deficient mice hints at a differential activation of neuronal cell survival pathways. Third, as no change in the density of tyrosine hydroxylase (TH)‐positive terminals in the striatum was observed, the remaining dopamine‐producing neurons likely compensate by increasing axonal sprouting. In summary, the present data suggest that DJ‐1 is implicated in major non‐motor symptoms of PD appearing in the early phases of the disease—such as subtle impairments in motivated behaviour and cognition—and that under basal conditions the loss of DJ‐1 is compensated
Selenoproteins are rare proteins among all kingdoms of life containing the 21st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for ...sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided.
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•Selenium-containing GPX4 is necessary for full viability of mice•The GPX4-Cys variant is highly susceptible to hydroperoxide-induced inactivation•Hydroperoxide induces ferroptosis in Gpx4cys/cys cells•GPX4-Cys bypasses the requirement of selenoproteins for cell viability
The trace element selenium protects a critical population of interneurons from ferroptotic cell death.
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