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Brain-Activity regulating protein

Science Daily

       UC Irvine researchers have found that a protein best known for building connections between nerve cells and muscle also plays a role in controlling brain cell activity. The finding points to possible therapeutic applications in the development of new drugs for treatment of epilepsy and neurodegenerative disorders.

       Martin Smith, professor of anatomy and neurobiology in the School of Medicine, and his UCI colleagues discovered that agrin -- a protein that directs synapse formation between nerve and muscle cells -- can also inhibit the function of "pumps" that control sodium and potassium levels within cells.

These pumps, called sodium-potassium ATPases -- or sodium pumps, for short -- are especially important in electrically excitable cells, where they provide the basis for electrical impulses, known as action potentials, which are responsible for muscle contraction and signaling between nerve cells in the brain. They do this by pumping sodium out of a cell and pumping potassium in, setting up an electrochemical gradient -- in a sense, turning the cell into a battery.

If this activity isn't properly moderated, uncontrollable electrical impulses can be triggered, which is one of the cellular mechanisms behind an epileptic seizure, for instance.

This is where agrin comes into action. The UCI researchers observed in laboratory tests that agrin controls the excitability of nerve cells in the brain by regulating sodium pump activity. Adding agrin caused nerve cells to fire electrical impulses uncontrollably. In turn, the researchers found that they could block these electrical impulses by introducing small fragments of agrin, which prevented the full agrin proteins from binding their sites on the sodium pump molecules and initiating action potentials.

"The ability of agrin to modulate nerve cell excitability suggests that the agrin-sodium pump interactions can be exploited as a novel therapeutic target for epilepsy and other brain disorders," Smith said.

Agrin proteins are also expressed in heart tissue, and Smith notes that sodium pump inhibitors, such as digoxin, are commonly used to treat congestive heart failure. Agrin may, therefore, have therapeutic value for the treatment of diseases affecting tissues and organs outside of the brain.

The study appears in the April 21 issue of Cell. Lutz Hilgenberg, Hailing Su, Huaiyu Gu and Diane O'Dowd of UCI collaborated on the study, which was supported by the National Institutes of Health.

UCI has filed for patents covering the use of agrin and its derivatives in treatment of epilepsy and other pathologies of the brain and as tools that could be used to screen for novel compounds that regulate sodium pump activity.

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Science of Ageing

World-Science

 

       Researchers say they have uncovered a mechanism behind the normal aging process, based on studies of children with a devastating “early-aging” disorder.

       Many scientists have speculated that certain premature-aging disorders, which can end children’s lives by their early teens, were somehow accelerated versions of normal aging. If so, then studying these conditions might have a side benefit for the rest of us, giving biologists a powerful way to understand, and perhaps “treat,” ordinary aging.

       But scientists previously had trouble finding clear links, at a detailed level, between these syndromes and normal aging. Superficial resemblances were obvious. For instance, children with the devastating Hutchinson-Gilford Progeria Syndrome “age” at seven times the normal rate, so a 10-year-old patient could have heart conditions and arthritis typical of a 70-year-old.

       But some scientists have downplayed the similarities to normal aging, because detailed analyses also reveal important differences. Nonetheless, in the new study, researchers linked Hutchinson-Gilford Progeria—the most drastic of the major premature-aging disorders—to normal aging, at a molecular level.

       Researchers had previously attributed the syndrome, currently incurable, to a mutation in a gene known as lamin A. The mutation leads the body to produce a defective, shortened version of a molecule by the same name that is part of the covering of the cell nucleus. Biologists are studying the abnormality in an effort to find treatments for the disorder.

       In the new study, P.a Scaffidi and Tom Misteli of the National Cancer Institute in Bethesda, Md., found that the same defect occurs sporadically in the cells of normally aged people. These cells, they reported, share some of the aberrations that occur in cell nuclei in people with the syndrome, such as unrepaired DNA damage. By blocking the defect in the molecules, the researchers said they were able to reverse some of the cellular abnormalities.

       The finding “suggests that lamin A participates in the aging process in healthy individuals,” they wrote, and that this process is “exaggerated” in the sick people. Thus, “this is a novel potential mechanism involved in aging,” Misteli wrote in an email. The findings appear in the April 27 issue of the research journal Science.
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Virus induced 'Autophagy'

World Science


       Researchers say they have engineered a virus that tracks down cancerous cells and forces them to devour themselves.

       The scientists, with the University of Texas M. D. Anderson Cancer Center in Houston, Texas, tested the treatment in mice with brain tumors. They described the results this week in the  Journal of the National Cancer Institute.

       The virus induced self-cannibalization among cancer cells, a process called autophagy, said the center’s Seiji Kondo. This shrank the tumors and extended the lives of the rodents, he added. 

       His team of researchers developed the treatment by modifying an adenovirus, one of a group of viruses that cause the common cold and various other infections.

       Among mice with brain tumors known as gliomas, those treated with three injections of the modified virus on average lived 53 days, the researchers said. Those that received a different, non-replicating adenovirus lived on average 29 days.

       Gliomas are the most common and deadly form of brain cancer, the researchers said.

       ‘‘This virus uses telomerase, an enzyme found in 80 percent of brain tumors, as a target,’’ Kondo said. ‘‘Once the virus enters the cell, it needs telomerase to replicate. Normal brain tissue does not have telomerase, so this virus replicates only in cancer cells.’’

       Other cancers are also associated with telomerase, the researchers said, adding that they found in lab experiments that the treatment may also work with prostate and cervical cancer.

       Besides showing the therapeutic potential of the virus, called hTERT-Ad, Kondo said his international research team also clarified how the modified viruses work.

       Autophagy is a natural, protective process that cells employ to consume part of themselves when nutrients are scarce, or to recycle their own worn-out components. A membrane forms around the material to be consumed, then everything inside is digested.

       Kondo and colleagues found that hTERT-Ad induced autophagy by inactivating a molecular pathway known to prevent the self-cannibalization.

       The pathway is distinct from apoptosis, a much better known process of programmed cellular “suicide.” A normal defense mechanism to systematically kill defective cells, apoptosis is dysfunctional in cancer cells. Many other cancer therapies focus on restoring or enhancing apoptosis to combat the disease.
Skeleton Key

World Science



       Researchers say they have found the genetic glitch behind a devastating disease that turns muscle to bone, eventually turning victims nearly into living “statues.”

        The rare condition, affecting an estimated 2,500 people worldwide, progressively converts more and more muscle, tendons and ligaments into bone. Eventually joints are locked into place, making movement impossible.

       The researchers, at the University of Pennsylvania School of Medicine, said they have been working for 15 years on identifying the gene, dubbed the “skeleton key.”
       The discovery is relevant not only for patients with the illness, called fibrodysplasia ossificans progressiva, or FOP, but for others with more common skeletal conditions, they said.

      Eileen Shore and Frederick Kaplan of the university, along with colleagues from other institutions, reported the findings in the April 23 advance online edition of the research journal Nature Genetics.

       The mutation, they found, involves a gene encoding a molecule called ACVR1.

       The disease begins in childhood, when tendons, ligaments, and skeletal muscle begin an inexorable transformation into an armament of bone. This bone “is perfectly normal in every way, except it should not be there,” Kaplan. “There are no other known examples of one normal organ system turning into another.”

       Victims seem normal at birth, except for telltale malformations of the great toes. Early in childhood, painful swellings often mistaken for tumors seize the skeletal muscles and turn them into bone.

       Eventually, ribbons, sheets, and plates of bone cross the joints and lock them into place. Surgically removing the extra bone just makes it grow back faster. Slight traumas such as bumps, bruises and injections can stimulate further transformation into bone.
       Victims often die, typically in their 40s, from complications related to difficulty breathing as the bone restricts the space available for their lungs to move. There is no effective treatment, other than avoiding much physical activity, but the researchers hope the gene’s discovery will change that.

       The condition, they said, results from a defect in a natural chain of molecular events called the bone morphogenetic protein signaling pathway, involved in the formation and repair of the skeleton.

       The molecule encoded by the newfound gene functions as a sort of “switch,” the scientists explained. The molecule appears in certain stem cells, immature cells that can develop into a variety of different cell types for diverse organs.

       The molecule consists of 509 subunits, called amino acids, of which one is defective in the condition, the researchers said: an amino acid known as histidine appears where another one, arginine, should be.

       This change somehow affects the activity of the “switch,” they explained, though understanding exactly how requires further study.

       “As is the case for most genes, every cell has two copies of the ACVR1 gene,” Shore said. In patients with the disease, one of the two harbors the mutation, which produces a defective version of the molecule.

       Whereas the defect in the molecule consists of a substituted amino acid, the defect in the gene itself—which produces that molecule—is a substituted “letter” of genetic code, called a nucleotide.

       “The substitution of one genetic letter for another out of six billion genetic letters in the human genome—the smallest and most precise change imaginable—is like a molecular terrorist,” said Kaplan.


Cooperator Gene

World Science
       Scientists have found that a one-letter change of DNA can transform a microbe with a habit of cheating its peers into a model citizen that cooperates with its bacterial comrades.

       Researchers have long been trying to untangle the evolutionary roots of cooperation and altruism. It’s a confounding problem, since evolutionary theory, at least superficially, suggests cheaters should triumph and do-gooders should die out.

       To attack the question, biologists have looked for the simplest possible examples of cases in which cooperation evolves, in order to study what fundamentally drives the process. In seeking out such a model, a scientist can hardly hope for better than one in which cooperation arises from the smallest possible type of genetic change, in what is perhaps the simplest sort of organism, bacteria.

       Gregory Velicer of the Max Planck Institute for Developmental Biology in Tübingen, Germany, and colleagues reported finding just that in strains of the soil-dwelling bacterium Myxococcus xanthus.

       During hard times, groups of M. xanthus join forces to form structures called fruiting bodies, in which they pool resources and produce hardy reproductive compartments called spores. Relatively few individuals survive, but the system lets the group wait out hardship and produce offspring that will emerge later.

       The arrangement is open to cheating by strains that don’t bother to form these aggregations, but nonetheless reap the benefits of the nutrients provided. Although “cheater” bacteria are thought to exist naturally in some species, Velicer’s team in this study produced freeloaders artificially, by cultivating some bacteria for 1,000 generations in easy conditions. There they “forgot” how to build the fruiting bodies, apparently losing the genes that enabled them to do so.
 
       When Velicer and colleagues mixed the cheating and socially responsible strains together under alternating conditions of stress and plenty, they said, they got a surprise. At first, an ever-growing number of freeloaders burdened the cooperative system, to the point that they eventually almost wiped out the population. Yet ultimately, a new, cooperative strain evolved that produced more surviving cells than either of the two original strains.

       The researchers christened the new strain Phoenix, because, as they explained, it rescued the bacterial population from the ashes of almost certain doom. They reported their findings in this week’s issue of the research journal Nature.

      “The new cooperator evolved from the cheater and not from the original cooperator,” Velicer wrote in an email. But “the new cooperator did not evolve a general ‘niceness’ to everyone. Cells of the new cooperator cooperate fully only with their own kind.”

      When the researchers sequenced the genes of the strains, they found that the cheaters’ newfound social conscience was due to a single-letter change in the DNA code.

      Kevin Foster of Harvard University, in an accompanying commentary in the journal, wrote that the experiment suggests that in a society disintegrating because of cheaters, evolution will favor mutations that bring back teamwork.

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