If stress goes on too long, it can lead to debilitating psychological problems. Part of the reason, according to scientists at the Rockefeller University, the United States, may have to do with a little-known family of proteins called kainate receptors that has recently been implicated in major depression. New research in rats may help explain one mechanism by which stress reshapes the brain: by ramping up production of a particular part of these proteins.

We have recently seen large human studies that suggest kainate receptors are targets for response to certain anti-depressants and are also involved in major depression and the susceptibility to suicidal thoughts, states Dr. Richard Hunter, a post-doctoral fellow in the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller. Dr. Hunter and his colleagues homed in on one of five subunits of the kainate receptor called KA1. Exploring the impact of stress and steroids on rats, they found that stress, simulated by restraining the rats for six hours a day for three weeks, caused the genes to send instructions messenger RNA to increase production of KA1 subunits in particular parts of the hippocampus, a highly plastic brain structure involved in learning and memory. Stress and depression are known to cause a reversible retraction of dendrites in certain brain cells, particularly in the hippocampus.

The lab produced a similar result by injecting unstressed rats with corticosteroids, suggesting that an increase in these hormones is largely responsible for the stress response in rats. But the researchers also found that the dose is critical. While a moderate amount of corticosteroids increased KA1 messenger RNA, a high dose of the steroids did not. The body seeks to maintain ideal levels, whether it is salts in the blood or any number of other things like KA1, remarks Dr. Hunter. Deviations to either side of these levels can cause pathologies or changes. The body adapts to changing circumstances to keep the levels healthy.

Earlier, Dr. Sidney Strickland, head of the Laboratory of Neurobiology and Genetics at Rockefeller, had shown that KA1 production explodes in the hippocampus during simulated stroke in mice, driving a cell-death cascade that begins when part of the brain is deprived of blood. Combined, the two works suggest that the relatively understudied KA1 subunit plays an important role in a key area of the brain in both causing damage in an uncontrolled trauma such as a stroke and in protecting the brain from damage under the more controlled circumstances of chronic stress.

Source: www.sciencedaily.com

Evidence found by researchers from the University of Rochester Medical Centre (URMC), the United States, links two proteins working in the brains blood vessels to Alzheimers disease. They have found that the proteins, serum response factor (SRF) and myocardin, reduce the rate of amyloid beta (A-beta) removal in the brain. The proteins work together to turn on a molecule known as sterol-responsive element-binding protein 2 (SREBP2), which then inhibits low-density lipoprotein-related protein 1 (LRP-1) that helps the body remove A-beta under normal conditions. This results in the accumulation of toxic levels of A-beta, aiding the progression of Alzheimers disease.

Although the scientists were surprised to find the two proteins, known for their role in the cardiovascular system, linked to the development of Alzheimers disease, a senior author of the study, Dr. Berislav Zlokovic from URMCs Centre for Neurodegenerative and Vascular Brain Disorders, said, ...both of these processes are mediated by the smooth muscle cells along blood vessel walls, and we know that those are seriously compromised in patients with Alzheimers disease. Dr. Joseph Miano, from URMCs Aab Cardiovascular Research Institute and senior co-author of the study added, There is a great deal of evidence to suggest that Alzheimers disease is a problem having much to do with the vascular plumbing.

The team studied brain cells taken from people who had Alzheimers and compared them to cells from healthy elderly people. Compared with the smooth muscle cells from healthy adults, the cells from patients with Alzheimers disease had about five times as much myocardin, about five times as much SREBP2, four times as much SRF, and about 60 per cent less LRP-1. That translates into a reduced ability to remove A-beta. Cells of patients with the disease had only about 30 per cent of the ability of their healthy counterparts to remove the substance.

When the team lowered levels of SRF to the same level that exists in healthy cells, the cells from Alzheimers patients improved in their ability to remove A-beta, doing it just as well as the cells from healthy individuals. Conversely, when the team boosted levels of SRF and myocardin in the healthy cells, the changes lowered by 65 per cent those cells ability to remove A-beta.

Source: www.genengnews.com

Scientists at A*STARs Institute of Molecular and Cell Biology (IMCB), Singapore, have become the first to discover and characterize a human protein called Bax-beta, which can potentially cause the death of cancer cells and lead to new approaches in cancer treatment. Said Dr. Victor Yu, principal investigator of the IMCB research team, Our research findings reveal that Bax-beta protein levels are normally kept at essentially undetectable levels in healthy cells by the protein degradation machine in cells known as proteasomes. Proteasomes are protein-digesting machines that regulate cellular levels of proteins including that of the lethal Bax-beta, by breaking them into smaller components within the cell.

Dr. Yu postulates that if the degradation of Bax-beta mediated by proteasome could be inhibited in cancer cells, it could cause the harmful cancer cells to self-destruct (apoptosis). While earlier evidence had suggested that more than one protein was encoded by the Bax gene, only a single protein called Bax-alpha had been extensively studied in cells. Dr. Yus team also found that Bax-beta is able to associate with, and promote Bax-alpha activation, and that Bax-beta, in its native form, is 100 times more potent than Bax-alpha in triggering a key step in apoptosis. The future development of novel compounds that can selectively elevate levels of Bax-beta or stimulate its interaction with Bax-alpha could lead to new drug approaches to cancer treatment.

Source: www.physorg.com

Researchers at the Massachusetts Institute of Technology, the United States, have discovered that the particular arrangement of proteins that produces the sturdiest product is not the arrangement with the most built-in redundancy or the most complicated pattern. Instead, the optimal arrangement of proteins in the rope-like structures they studied is a repeated pattern of two stacks of four bundled alpha-helical proteins. This composition of two repeated hierarchies (stacks and bundles) provides great strength, the ability to withstand mechanical pressure without giving way, and great robustness, the ability to perform mechanically.

Dr. Markus Buehler and Dr. Theodor Ackbarow, in a paper published in Nanotechnology, describe a model of the proteins performance, based on molecular dynamics simulations. With their model, they tested the strength and robustness of four different combinations of eight alpha-helical proteins: a single stack of eight proteins, two stacks of four bundled proteins, four stacks of two bundled proteins, and double stacks of two bundled proteins. Their molecular models replicate realistic molecular behaviour, including hydrogen bond formation in the coiled spring-like alpha-helical proteins.

Source: www.bio-medicine.org

Researchers have constructed a protein out of amino acids not found in natural proteins, discovering that they can form a complex, stable structure that closely resembles a natural protein. The findings could help scientists design drugs that look and act like real proteins but will not be degraded by enzymes or targeted by the immune system, as natural proteins are.

The scientists, led by Prof. Alanna Schepartz of the Howard Hughes Medical Institute, Yale University, the United States, built the short protein, or peptide, from beta-amino acids, which, although they exist in cells, are never found in ribosomally produced proteins. Beta-amino acids differ from the beta-amino acids that compose natural proteins by the addition of a single chemical component a methylene group into the peptide backbone.
The fundamental insight from this study is that beta-peptides can assemble into structures that generally resemble natural proteins in shape and stability, Prof. Schepartz said. Their findings on the structure of the molecule that the scientists synthesized would help construct more elaborate beta-peptide assemblies and ones that possess true biologic function. Such beta-peptides could also be designed as drugs that would be more effective than natural protein drugs, because the enzymes that degrade natural proteins will not affect them.

In their studies, Prof. Schepartz and colleagues synthesized a beta-peptide they called Zwit1-F. They allowed the chain of beta-amino acids to assemble into its own structure and then analysed it with X-ray crystallography. They found that the Zwit1-F peptide folded into a bundle of coiled helices that resembled those in natural proteins. In particular, they noted that both natural proteins and the beta-peptide bundle folded in ways that placed the hydrophobic segments of the molecule in the core of the structure. Other features, too, were remarkably similar to a coiled helix bundle formed of beta-amino acids.

There were major differences too. For instance, when helices of natural peptides nestle against one another, often their side chains extend from the sides of each helix, fitting together like ridges in grooves. The beta-peptide helices, however, are structured so that their side chains alternate like interlocking fingers.

Source: www.physorg.com