The loss of a particular gene (CHRNA7) through deletion of genetic material on chromosome 15 appears to be associated with significant abnormalities in learning and behavior, according to a recent report by Baylor College of Medicine (BCM) researchers and colleagues. “This research goes about 95 percent of the way to pinning these problems in a specific group of individuals to this gene,” said Dr. Arthur Beaudet, chair of molecular and human genetics at BCM and an author of the report. Dr. Beaudet believes that the deletion will be identified in other people with behavioral problems, as well as schizophrenia, developmental delay, and epilepsy. The gene’s role in schizophrenia has been under study for some time. “This gene encodes a subunit of a nicotinic receptor,” Dr. Beaudet said. “It is a gene that mediates the response to nicotine via a receptor whose normal ligand is acetylcholine.” The gene encodes a protein called an ion channel, which allows ions to flow in and out of neurons in the brain. Defects in ion channels have previously been associated with forms of epilepsy or seizure disorder. “If insufficient expression of the nicotinic receptor causes most or all of the problems associated with deletions in this particular area of chromosome 15, then it offers a target for drug treatment,” said Dr. Pawel Stankiewicz, senior author of the report. One such drug mentioned in the paper is Chantix, a medicine now used in smoking cessation efforts. This work was published online on November 8 in Nature Genetics. [Press release] [Nature Genetics abstract]
Simple Blood Test May Identify Women at Risk of Alzheimer’s
Middle-aged women with high levels of a specific amino acid (homocysteine) in their blood are twice as likely to suffer from Alzheimer’s disease many years later, according to a recent thesis from the Sahlgrenska Academy at the University of Gothenburg, Sweden. This discovery could lead to a new and simple way of determining who is at risk long before there are any signs of the illness. The thesis is based on the Prospective Population Study of Women in Gothenburg, which was started at the end of the 1960s when almost 1,500 women between the ages of 38 and 60 were examined, asked questions about their health, and had blood samples taken. Nearly all of the samples have now been analyzed and compared with information on who went on to suffer from Alzheimer’s and dementia much later. “Alzheimer’s disease was more than twice as common among the women with the highest levels of homocysteine than among those with the lowest, and the risk for any kind of dementia was 70 per cent higher,” said Dr. Dimitri Zylberstein, author of the thesis. Historically, elevated homocysteine levels have been related to certain vitamin deficiencies (B12 and folate). Today we know that high homocysteine levels might be present even with perfectly normal vitamin status. “These days we in our clinical practice use homocysteine analyses mainly for assessment of vitamin status. However, our results mean that we could use the very same analysis for assessment of an individual’s risk profile for dementia development. This opens the possibility for future preventive treatment at a very early stage,” said Dr. Zylberstein. [Press release]
Scientists Target DNA Quadruplexes in Battle Against Cancer
Some designers of anti-cancer drugs are investigating mysterious chunks of the genetic material DNA that may play a key role in preventing the growth and spread of cancer cells, according to an article in the November 2 issue of Chemical & Engineering News, the weekly newsmagazine of the American Chemical Society. In the article, C&EN Deputy Assistant Managing editor Stu Borman notes that the DNA structures, which scientists term “quadruplexes” because they have four-sided structures, are a genre of folded DNA that may help control whether genes are switched on or off. Quadruplexes sometimes form near genes that foster the growth of cancer cells. Some scientists thus regard them as promising targets for developing new anti-cancer drugs. Drugs that interact with quadruplexes could help kill cancer cells without harming healthy cells. In addition, they may side-step the serious problem of drug resistance, in which some drugs gradually lose their effectiveness against cancer. The C&EN article describes research on quadruplex-targeted drugs and explores the mysteries about how quadruplexes form, disappear, and function. [Press release] [C&EN article]
Reconstitution of Enzyme Synthesizing Lovastatin Precursor
Researchers from UCLA, and colleagues, have for the first time successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. “In this study, we studied the enzyme that makes a small-molecule precursor to lovastatin. And what’s really different about this enzyme, compared to all other enzymes people have studied, is that this enzyme is extraordinarily large,” said Dr. Yi Tang, senior author of the study. “It’s one of the largest enzymes ever to be reconstituted in a test tube. It is ten times the size of most enzymes people study.” The enzyme used in Dr. Tang’s study has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Dr. Tang’s team has been able to recapture all of the steps needed to make the lovastatin precursor molecule. “It’s like having an assembly line with seven stations, and in one round you have to go through a combination of these seven stations. Remarkably, this enzyme uses the assembly line eight times to make this small molecule—every time, it uses a different combination of the individual stations,” Dr. Tang said. “So the large enzyme is programmed to utilize these stations differentially at every cycle, in different combinations, and now we can do it in a test tube.” And with this, Dr. Tang hopes they will be able to disrupt, tweak, and change some of the steps to make slightly different molecules that can be just as beneficial. “It’s biosynthetic engineering of an assembly line to make a molecule that nature doesn’t make,” Dr. Tang said.
Agent Inhibits Breast Cancer Metastasis to Bone
Researchers have reduced breast cancer metastasis to bone by using an experimental agent to inhibit ROCK (Rho-associated kinase), a protein that was found to be over-expressed in metastatic breast cancer. In a study in mice, a team of researchers from Tufts University reported that inhibiting ROCK in the earliest stages of breast cancer decreased metastatic tumor mass in bone by 77 percent and overall frequency of metastasis by 36 percent. The results suggest that ROCK may be a target for new drug therapies to reduce breast cancer metastasis. “While the primary tumor causes significant illness and requires treatment, metastasis accounts for over 90 percent of breast cancer-related deaths. There are no treatments to eradicate metastasis. Establishing ROCK’s role in the spread of breast cancer and identifying agents to inhibit ROCK brings us one step closer to an approach that might reduce metastasis in the future,” said senior author Dr. Michael Rosenblatt. Breast cancer is the second leading fatal cancer in women, and affects just under one in eight women in the United States. Bone is the most common site of breast cancer metastasis, affected three times more often than the lungs or liver. The study was published online on November 3 in Cancer Research. [Press release] [Cancer Research abstract]
Antibody Gene Therapy Shows Promise in Mouse Models of Huntington’s Disease
Researchers at the California Institute of Technology have shown that a highly specific intrabody (an antibody fragment that works against a target inside a cell) is capable of stalling the development of Huntington’s disease in a variety of mouse models. “Gene therapy in these models successfully attenuated the symptoms of Huntington’s disease and increased life span,” noted Dr. Paul Patterson, the senior author of the study. The intrabody, called Happ1, targets an amino acid sequence unique to the huntingtin protein that is rich in the amino acid proline. Because of this, the action of Happ1 is expected to be extremely specific. “Our studies show that the use of intrabodies can block the parts of mutant huntingtin that cause its toxicity without affecting the wild type, or normal, huntingtin—or any other proteins,” said Dr. Patterson. In other words, he said, this approach has the potential to be the kind of “silver-bullet therapy” that many medical researchers look for. With regard to future work, Dr. Patterson said, “we need to improve the efficacy of the intrabody, and we need to build a viral vector that can be controlled—induced and turned off—in case of unexpected side effects. This is a general goal shared by all types of experimental gene therapies.” This work was published in the October 28 issue of the Journal of Neuroscience. [Press release] [Journal of Neuroscience abstract]
Blood-Starved Retinal Cells May Regain Function
Researchers at Johns Hopkins, together with collaborators, have found that when some cells in the mouse retina are not properly fed by blood vessels, they can remain alive for many months and can later recover some or all of their normal function, suggesting that similar conditions in people may also be reversible. “This finding is intriguing,” said Dr. Jeremy Nathans, senior author of the study, and a professor of molecular biology and genetics, neuroscience, and ophthalmology at Johns Hopkins and a Howard Hughes Medical Institute investigator. “It suggests that neurons in the retina can survive for an extended period of time even though they have been functionally silenced. If the human retina responds to a decrease in blood supply in the same way that the mouse retina responds, then these results may have relevance for those patients with vision loss due to vascular defects,” said Dr. Nathans. “In particular, these experiments suggest that if a region of the retina has been deprived of its normal blood supply, then completely or partially restoring that supply may also restore some visual function, even if this happens weeks or months later.” The report appeared in the October 16 issue of Cell. [Press release] [Cell abstract]
Convergent Evolution of Toxins Seen in Shrew and Lizard
Biologists at Harvard University and Massachusetts General Hospital have shown that independent, but similar, molecular changes turned a harmless digestive enzyme into a toxin in two unrelated species–a shrew and a lizard–giving each a venomous bite. “The venom is essentially an overactivation of the original digestive enzyme, amplifying its effects,” said Dr. Yael T. Aminetzach, lead author of the study. “What had been a mild anticoagulant in the salivary glands of both species has become a much more extreme compound that causes paralysis and death in prey that is bitten.” In the first part of the study, Dr. Aminetzach and her colleagues compared a toxin found in the salivary glands of the insectivorous North American shrew (Blarina brevicauda) to its closely related digestive enzyme kallikrein. Dr. Aminetzach found that the specific molecular differences between kallikrein and its toxic descendent are highly localized around the enzyme’s active site. “Catalysis is fostered by three specific changes that increase enzyme activity,” Dr. Aminetzach said. “The active site is physically opened up, and the loops surrounding it become more flexible. The area around the active site also becomes positively charged, serving to better guide the substrate directly into the active site.” To further demonstrate that these molecular changes to kallikrein are related to the evolution of toxicity, Aminetzach explored the evolution of another kallikrein-like toxin in the Mexican beaded lizard (Helodermata horridum) (male and female shown in photo). She found that this toxin, while distinct from the analogous toxin in the shrew, nonetheless exhibits the same catalytic enhancement relative to the original kallikrein enzyme.
Drug-Radiation Combination Eradicates Lung Cancer in Mice
Combination of an investigative drug (BEZ235) and low-dose radiation eliminates non-small cell lung cancer (NSCLC) in mice, according to results of a recent study conducted by researchers at the University of Texas Southwestern Medical Center, and collaborators including Novartis Pharma. NSCLC is a leading cause of cancer-related deaths worldwide. The researchers found that if they administered BEZ235 before they damaged the DNA of tumor cells with otherwise nontoxic radiation, the drug blocked the pro-survival actions of a protein called PI3K, which normally springs into action to keep tumor cells alive while they repair DNA damage. The researchers tested their novel therapeutic strategy in mice transplanted with NSCLC cells obtained from patients. They found that tumors in the mice treated with BEZ235 alone were significantly smaller than those in mice not given the drug. Although the tumors stopped growing, they did not die. By contrast, tumors were completely eradicated in mice treated with a combination of BEZ235 and radiation. “These early results suggest that the drug-radiation combination might be an effective therapy in lung cancer patients,” said Dr. Pier Paolo Scaglioni, senior author of the study. The report was published in the October 1 issue of Cancer Research. [Press release] [Cancer Research abstract]
Pumpkin Scares Off Microbes
Pumpkin rinds contain a substance with an antibacterial effect against microbes that cause millions of cases of yeast infections in adults and infants each year, according to a recent research report. The researchers noted that some disease-causing microbes are becoming resistant to existing antibiotics. As a result, scientists worldwide are searching for new antibiotics. Past studies have hinted that pumpkin, long used as a folk medicine in some countries, might have antibiotic effects. The researchers extracted proteins from pumpkin rinds to see if the proteins inhibit the growth of microbes, including Candida albicans. That fungus causes vaginal yeast infections, diaper rash in infants, and other health problems. One pumpkin protein had powerful effects in inhibiting the growth of C. albicans, in cell culture experiments, with no obvious toxic effects. The protein could be developed into a natural medicine for fighting yeast infections in humans, the report suggested. The protein also blocked the growth of several fungi that attack important plant crops and could be useful as an agricultural fungicide, the researchers added. The report was published in the October 14 issue of the Journal of Agricultural and Food Chemistry, an ACS publication. [Press release] [JAFC abstract]