The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex.

Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. TeNT binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. While the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear.

Biallelic Loss-of-Function Variants in Are Associated with Peripheral Neuropathy and Hearing Loss.

Hearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control.

[Effects of Sodium Selenite and Dithiothreitol on Expression of Endoplasmic Reticulum Selenoproteins and Apoptosis Markers in MSF7 Breast Adenocarcinoma Cells].

The endoplasmic reticulum (ER) stress inducers dithiothreitol (DTT) and sodium selenite (SS) were tested for effect on expression of ER selenoproteins and apoptosis markers in MCF7 breast adenocarcinoma cells. DTT used at 1 or 5 mM did not affect the survival of MCF7 cells. Based on the real-time PCR data and the protein expression levels of ER stress markers, ER stress was assumed to evolve along an adaptation pathway in MCF7 cells treated with 1 or 5 mM DTT, involving mainly the transcription factors IRE1 and ATF6 and the selenoproteins SELS, SELK, SELT, SELM, and SELN.

Activation of Signal Pathways of Apoptosis under Conditions of Prolonged ER-Stress Caused by Exposure of Mouse Testicular Teratoma Cells to Selenium-Containing Compounds.

Aim to study the molecular mechanisms of apoptotic death of mouse testicular teratocarcinoma cells (line F-9) under exposure to the widely used selenium-containing compounds with antitumor activity, sodium selenite and methylseleninic acid. Methods fluorescence microscopy, MTT assay, Western blotting. Results It was shown that sodium selenite at a concentration of 10 μM and methylseleninic acid at concentrations of 1 and 10 μM cause apoptosis-dependent death of F-9 cells, excluding necrotic death.

Effects of low-level combined static and weak low-frequency alternating magnetic fields on cytokine production and tumor development in mice.

We investigated the effects of weak combined magnetic fields (MFs) produced by superimposing a constant MF (in the range 30 - 150 µT) and an alternating MF (100 or 200 nT) on cytokine production in healthy Balb/C male mice exposed 2 h daily for 14 days. The alternating magnetic field was a sum of several frequencies (ranging from 2.5 - 17.

Influence of Sodium Selenite on the mRNA Expression of the Mammalian Selenocysteine-Containing Protein Genes in Testicle and Prostate Cancer Cells.

The sodium selenite concentration that reduces the viability of Du-145 human prostate adenocarcinoma cells and F-9 mouse testicular teratocarcinoma cells was determined. We investigated the effect of sodium selenite on the mRNA expression level of the genes encoding mammalian selenocysteine-containing glutathione peroxidases and thioredoxin reductases (key antioxidant enzymes involved in the regulation of intracellular thiol redox balance), endoplasmic reticulum selenoproteins, and selenoproteins located in the testes and prostate.

The travel diaries of tetanus and botulinum neurotoxins.

Tetanus (TeNT) and botulinum (BoNT) neurotoxins, the causative agents of tetanus and botulism, respectively, are the most potent toxic molecules known to mankind. This extreme potency is attributed to: i) their specificity for essential components of the neurotransmitter release machinery present at vertebrate synapses, and ii) their high-affinity targeting to motor neurons by binding to polysialogangliosides and protein receptors. Comprising the clostridial neurotoxin family, TeNT and BoNTs engage distinct surface receptors and intracellular sorting pathways in neurons.

[Methods to Biosynthesize Mammalian Selenocysteine-Containing Proteins in vitro].

The main problem in studying mammalian selenocysteine-containing proteins is that the proteins are difficult to obtain in a recombinant form because the amino acid selenocysteine (Sec), which is their component, is encoded by TGA, which is one of the stop codons. When only the open reading frame of a target protein is cloned in a plasmid, translation is prematurely terminated at the TGA codon. An intricate natural mechanism allows the codon to be recognized as a selenocysteine codon and involves various cis- and trans-acting factors, such as the selenocysteine insertion sequence (SECIS), mRNA secondary structure, selenocysteine tRNA Sec-tRNA^( [Ser]Sec), SECIS-binding protein 2 (SBP2), selenocysteine-specific elongation factor EFsec, and others.

The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis.

Detergent-resistant, ubiquitinated and hyperphosphorylated Tar DNA binding protein 43 (TDP-43, encoded by TARDBP) neuronal cytoplasmic inclusions are the pathological hallmark in ∼95% of amyotrophic lateral sclerosis and ∼60% of frontotemporal lobar degeneration cases. We sought to explore the role for the heat shock response in the clearance of insoluble TDP-43 in a cellular model of disease and to validate our findings in transgenic mice and human amyotrophic lateral sclerosis tissues. The heat shock response is a stress-responsive protective mechanism regulated by the transcription factor heat shock factor 1 (HSF1), which increases the expression of chaperones that refold damaged misfolded proteins or facilitate their degradation.

[cDNA cloning, expression and determination of substrate specificity of mice selenocysteine-containing protein SelV (Selenoprotein V)].

To date various bioinformatics tools allowed to identify 25 selenocysteine-containing mammalian proteins. The name of these proteins assumes that they contain the amino acid selenocysteine (Sec). Functionally characterized selenocysteine-containing proteins are oxidoreductases with various functions, including glutathione peroxidases, thioredoxin reductases, deiodinases etc.

[Characterization of some thiol oxidoreductase family members].

There are no doubt about the important role of free radicals and reactive oxygen species in the processes of cell activity. The disturbances of intracellular redox processes are often accompanied with the development of such common pathologies as diabetes, myocardial infarction, neurodegeneration, broncho-pulmonary diseases, cancer, etc. To date, there are a large number of antioxidant enzymes related to different redox biology systems, the key role among them is played by enzymes belong to the thiol oxidoreductases superfamily, which consists of thioredoxin, glutaredoxin, peroxiredoxin, protein disulfidizomeraz, glutathione peroxidase families, and a number of other proteins.

Hsp90 inhibition protects against inherited retinal degeneration.

The molecular chaperone Hsp90 is important for the functional maturation of many client proteins, and inhibitors are in clinical trials for multiple indications in cancer. Hsp90 inhibition activates the heat shock response and can improve viability in a cell model of the P23H misfolding mutation in rhodopsin that causes autosomal dominant retinitis pigmentosa (adRP). Here, we show that a single low dose of the Hsp90 inhibitor HSP990 enhanced visual function and delayed photoreceptor degeneration in a P23H transgenic rat model.

Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in superoxide dismutase (SOD1) are associated with familial ALS and lead to SOD1 protein misfolding and aggregation. Here we show that the molecular chaperone, HSJ1 (DNAJB2), mutations in which cause distal hereditary motor neuropathy, can reduce mutant SOD1 aggregation and improve motor neuron survival in mutant SOD1 models of ALS.

[Development of the system of dietary nutrition in the Armed Forces of the Russian Federation].

The analysis of the existing system of organization dietary personnel in the Armed Forces has been done. The new system of improvement of dietary nutrition for military personnel was developed. This system is based on scientifically proven food rationings that provide a balance of nutrients and mechanical and chemical sparing of GI tract.

The cell stress machinery and retinal degeneration.

Retinal degenerations are a group of clinically and genetically heterogeneous disorders characterised by progressive loss of vision due to neurodegeneration. The retina is a highly specialised tissue with a unique architecture and maintaining homeostasis in all the different retinal cell types is crucial for healthy vision. The retina can be exposed to a variety of environmental insults and stress, including light-induced damage, oxidative stress and inherited mutations that can lead to protein misfolding.

Contrasting roles of dietary selenium and selenoproteins in chemically induced hepatocarcinogenesis.

Selenium (Se) has long been known for its cancer prevention properties, but the molecular basis remains unclear. The principal questions in assessing the effect of dietary Se in cancer are whether selenoproteins, small molecule selenocompounds, or both, are involved, and under which conditions and genotypes Se may be protective. In this study, we examined diethylnitrosamine-induced hepatocarcinogenesis in mice lacking a subset of selenoproteins due to expression of a mutant selenocysteine tRNA gene (Trsp (A37G) mice).

NUB1 modulation of GSK3β reduces tau aggregation.

Abnormal phosphorylation of the microtubule-associated protein tau in neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration, is associated with disrupted axonal transport and synaptic dysfunction ultimately manifesting as histopathological lesions of protein aggregates. Glycogen synthase kinase 3β (GSK3β) may be critical for the pathological hyperphosphorylation of tau. Here, we examined the role of the proteasome-associated protein Nedd8 ultimate buster 1 (NUB1) in the neuropathogenic phosphorylation and aggregation of tau.

BiP prevents rod opsin aggregation.

Mutations in rod opsin-the light-sensitive protein of rod cells-cause retinitis pigmentosa. Many rod opsin mutations lead to protein misfolding, and therefore it is important to understand the role of molecular chaperones in rod opsin biogenesis. We show that BiP (HSPA5) prevents the aggregation of rod opsin.

Suppression of protein aggregation by chaperone modification of high molecular weight complexes.

Protein misfolding and aggregation are associated with many neurodegenerative diseases, including Huntington's disease. The cellular machinery for maintaining proteostasis includes molecular chaperones that facilitate protein folding and reduce proteotoxicity. Increasing the protein folding capacity of cells through manipulation of DNAJ chaperones has been shown to suppress aggregation and ameliorate polyglutamine toxicity in cells and flies.

Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain mutant.

Mitochondrial dysfunction is characteristic of many neurodegenerative diseases. The Parkinson's disease-associated ubiquitin-protein ligase, Parkin, is important in the elimination of damaged mitochondria by autophagy (mitophagy) in a multistep process. Here, we show that a Parkin RING domain mutant (C289G) fails to redistribute to damaged mitochondria and cannot induce mitophagy after treatment with the mitochondrial uncoupler carbonyl cyanide m-methylhydrazone, because of protein misfolding and aggregation.

Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies.

Background: Recent studies highlight the role of endoplasmic reticulum (ER) stress and aberrant protein degradation in the pathogenesis of neurodegenerative disorders. Herp which is encoded by the HERPUD 1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1) gene is a stress-response protein localized in the ER membrane of neurons and other cell types. Herp has been suggested to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD) of proteins.

Regulation of selenoproteins and methionine sulfoxide reductases A and B1 by age, calorie restriction, and dietary selenium in mice.

Methionine residues are susceptible to oxidation, but this damage may be reversed by methionine sulfoxide reductases MsrA and MsrB. Mammals contain one MsrA and three MsrBs, including a selenoprotein MsrB1. Here, we show that MsrB1 is the major methionine sulfoxide reductase in liver of mice and it is among the proteins that are most easily regulated by dietary selenium.

MsrB1 (methionine-R-sulfoxide reductase 1) knock-out mice: roles of MsrB1 in redox regulation and identification of a novel selenoprotein form.

Protein oxidation has been linked to accelerated aging and is a contributing factor to many diseases. Methionine residues are particularly susceptible to oxidation, but the resulting mixture of methionine R-sulfoxide (Met-RO) and methionine S-sulfoxide (Met-SO) can be repaired by thioredoxin-dependent enzymes MsrB and MsrA, respectively. Here, we describe a knock-out mouse deficient in selenoprotein MsrB1, the main mammalian MsrB located in the cytosol and nucleus.