Syndicate content

Protective Gene Variant Identified for Lou Gehrig’s Disease

A gene variant that extends the survival time in amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, by as much as 50 percent has been identified by an international team of researchers. "This report is the first to describe genetic factors that determine rate of progression in ALS," said Dr. Robert Brown, one of the study leaders. The gene is KIFAP3 and researchers know that it is involved in a number of cellular processes, including the transport of essential molecules throughout the nerve cell. "The favorable gene variant decreases levels of a motor protein complex in nerves," said Dr. John Landers, also a leader of the study. "This complex transports substances through different parts of nerve cells. If we can understand the biological basis for the beneficial effect in ALS, it will potentially provide a target for the development of new ALS treatments.” Because survival with ALS is normally only three to five years, patients with the KIFAP3 gene variant experience a substantial improvement. In fact, the researchers suggested that impact of this genetic variant is comparable to the effect of the only drug (Riluzole) now approved for use in ALS in the United States. More importantly, this genetic variant may potentially point the way to future drug development efforts. This work is reported in PNAS. [Press release]

Novel Potassium Channel Implicated in Schizophrenia

Expression of a previously unknown, primate-specific, and brain-specific isoform (3.1) of a key potassium channel protein (KCNH2) that modulates neuronal firing was found to be 2.5-fold higher than normal in the hippocampus (brain memory hub) of people with schizophrenia, especially in those with schizophrenia risk-associated variations in the KCNH2 gene, according to a recent report. KCNH2-3.1 isoform levels were also found to be higher than normal in healthy individuals who carried the risk-associated KCNH2 gene variations, and these individuals were shown to exhibit some schizophrenia-like effects in brain circuitry and mental processing, even though they do not show psychotic behavior. "Our study goes further [than gene association studies], spanning discovery of a new gene variant, confirmation of its association with the illness, and multi-level probes into how it works--in human post-mortem brain tissue, the living human brain, and neurons," said Dr. Daniel Weinberger, director of the National Institute of Mental Health's Genes Cognition and Psychosis Program. An extensive series of experiments suggest that selectively inhibiting the KCNH2-3.1 isoform could help correct disorganized brain activity in schizophrenia, without risk of the cardiac side effects associated with some existing antipsychotic medications. This work was reported in the May issue of Nature Medicine. [NIH release] [Nature Medicine abstract]

Most Common Protein in Urine Associated with Altered Kidney Disease Risk

An international research team has shown that a common genetic variant of the gene (UMOD) for the most common protein in normal human urine is associated with a lowered risk of chronic kidney disease. This protein is the Tamm-Horsfall protein and, although it has been known for almost 60 years, its functions are not well understood and its relationship to chronic kidney disease risk was not known previously. "Previous research showed that rare mutations in the UMOD gene cause hereditary forms of severe kidney disease. Our research indicates that a common genetic variant with a frequency of 18 percent in populations of European ancestry is associated with about 25 percent lower risk of chronic kidney disease," said the lead author of the study, Dr. Anna Köttgen, a researcher in the Johns Hopkins Bloomberg School of Public Health. In their genome-wide association studies, the researchers also identified two additional genes (SHROOM3 and STC1) that were associated with altered risk for reduced kidney function and chronic kidney disease. The study was published in the May 10 online edition of Nature Genetics. [Johns Hopkins release] [Nature Genetics abstract]

Blocking Single Target May Prevent Lethal Aneurysms

Researchers have shown that removal of a single key protein can prevent early damage in blood vessels from triggering a later-stage, frequently lethal complication of atherosclerosis. By eliminating the gene for a signaling protein called cyclophilin A (CypA) from a strain of mice, the team was able to provide complete protection against abdominal aortic aneurysm (AAA). AAA leads to 15,000 deaths a year, mostly in aging men, when aneurysms rupture to spill blood into the abdomen, a fatal event in 90 percent of cases. When study mice were engineered to remove their CypA gene, none from that group developed AAA in the face of the hypertension and high cholesterol known to accelerate it. In contrast, 78 percent of mice with "normal" amounts of CypA developed AAA under the same conditions, 35 percent with a fatal rupture. The researchers also found high CypA levels in the rupture-prone vessels of humans with AAA, and that major drugs like statins reduce CypA levels, which may partly explain their benefit. “It is extremely unusual for the removal of one protein to provide absolute protection, but it makes perfect sense because cyclophilin A promotes three of the most destructive forces in blood vessels: oxidative stress, inflammation, and matrix degradation," said Dr. Bradford C. Berk, of the Aab Cardiovascular Research Institute at the University of Rochester Medical Center, and senior author of the study. "We are working to design anti-CypA drugs that will diminish the disease processes underlying AAA, atherosclerosis and hypertension." This study was published in the May 10 online edition of Nature Medicine. [Press release] [Nature Medicine abstract]

Alcohol Flushing Response May Indicate Cancer Risk

The alcohol flushing response, seen in approximately 36% of East Asians (Japanese, Chinese, and Koreans), may be an indictor of a much increased risk of esophageal cancer from alcohol consumption in these individuals, according to a recent article in PLoS Medicine. This is particularly unfortunate as esophageal cancer is one of the deadliest cancers worldwide, with five-year survival rates of 15.6% in the United States, 12.3% in Europe, and 31.6% in Japan, the authors noted. The flushing response is predominantly due to an inherited deficiency in the enzyme alcohol dehydrogenase 2 (ALDH2), and there is accumulating evidence that individuals deficient in ALDH2 are at a much higher risk of esophageal cancer than are those with normal levels of ALDH2. The authors advised that doctors should counsel their ALDH2-deficient patients to limit alcohol consumption and thereby reduce the risk of developing esophageal cancer. Clinicians can determine ALDH2 deficiency simply by asking about previous episodes of alcohol-induced flushing. As a result, ALDH2-deficient patients can then be counseled to reduce alcohol consumption, and high-risk patients can be assessed for endoscopic cancer screening. In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in esophageal cancers due to a reduction in alcohol drinking would translate into a substantial number of lives saved, the authors asserted. [PLoS Medicine article]

Gecko’s Night Vision May Be Basis for Better Cameras, Contact Lenses

The key to the exceptional night vision of the nocturnal helmeted gecko is a series of distinct concentric zones of different refractive powers, according to a study published in the online Journal of Vision. Nocturnal geckos are among the very few living creatures able to see colors at night. "We were interested in the geckos because they, and other lizards, differ from most other vertebrates in having only cones in their retina," said project leader Dr. Lina Roth of Lund University in Sweden. "With the knowledge from the gecko eyes, we might be able to develop more effective cameras and maybe even useful multifocal contact lenses." The nocturnal gecko’s multifocal optical system is comprised of large cones, which the researchers calculated to be more than 350 times more sensitive than human cone vision at the human color vision threshold. The nocturnal gecko’s optical system gives them an advantage because light of different ranges of wavelengths can be focused simultaneously on the retina. Another possible advantage is that their eyes allow them to focus on objects at different distances. Therefore, the multifocal eye would generate a sharp image for at least two different depths. Geckos that are active during the day do not possess the distinct concentric zones and are considered monofocal, the researchers said. [Press release] [Journal of Vision abstract]

Source of Silkworm Attraction to Mulberry Leaves Discovered

Scientists have discovered the source of the silkworm’s attraction to mulberry leaves, their primary food source. A jasmine-scented chemical (cis-jasmone) emitted in small quantities by the leaves triggers a single, highly tuned olfactory receptor in the silkworms’ antennae, the researchers showed. The results are contrary to the prevailing belief that insects are generally attracted to their host plants through the recognition of a blend of volatile compounds by a combination of receptors, said Dr. Kazushige Touhara of The University of Tokyo, the senior author of the report. In addition to the new insights into insect olfaction, the findings may also have practical implications for those who raise silkworms for the production of silk, he added. The study was published online on May 7 in Current Biology. [Press release] [Current Biology abstract]

Sanfilippo Syndrome Might Be Treatable with Alzheimer Drugs

Scientists at UCLA have obtained evidence that a form of the rare genetic disease known as Sanfilippo syndrome may be treatable with new Alzheimer’s disease drugs directed against the P-tau protein. Four different enzyme deficiencies cause Sanfilippo syndrome, leading to the disorder's classification as type A, B, C, or D. The UCLA team studied type B, the second most common form, which causes severe mental retardation, dementia, and death as early as age 14. "We knew that Sanfilippo syndrome type B results from a mutation of the gene that produces the enzyme needed to break down sugar molecule chains [mucopolysaccharides] in the body," said Dr. Elizabeth Neufeld, of the David Geffen School of Medicine at UCLA, and senior author of the study. "We studied the disease in mice bred to possess the same gene defect seen in human patients." Neufeld's team found that mice with the defective gene produce higher amounts of two proteins called lysozyme and P-tau. They tracked the proteins to neurons in the medial entorhinal cortex, an important memory center in the brain. This is one of the first areas to be affected by Alzheimer's disease, and the region also has been implicated in abnormalities in Sanfilippo syndrome. Earlier research had linked high levels of lysozyme to the production of P-tau, a misshapen protein that helps form the strands that clump into tangles in the brain. These tangles impair neuron function and are a hallmark of Alzheimer's and other degenerative brain diseases. "This is really exciting," said Dr. Stanislav Karsten, also an author of the study. "If we can replicate our discovery of P-tau in the brains of human patients, it may be possible to treat Sanfilippo syndrome with new drugs created for Alzheimer's disease.

Marker in Surrounding Tissue Is Prognostic in Breast Cancer

Researchers have shown that a marker in tissue surrounding tumor cells is a new prognostic factor for patients with breast cancer. Absence of the market (caveolin-1) in stromal fibroblasts is associated with early disease recurrence, metastasis, and decreased patient survival. Stroma is non-cancerous connective tissue, which, in solid tumors, surrounds tumor cells. “The idea that a prognostic biomarker is present in the stroma rather than the epithelial cancer cell is paradigm-shifting," said Dr. Michael Lisanti, the senior of the study and editor-in-chief of the American Journal of Pathology. “Importantly, these findings could be developed into a diagnostic test that would not require DNA-based technologies. This inexpensive and cost-effective test would allow doctors to identify high-risk breast cancer patients at diagnosis and treat them more aggressively.” The absence of caveolin-1 in the stroma also appeared to be a marker for drug resistance in patients receiving the anti-cancer drug tamoxifen, the researchers said. “These are significant findings that do have to be validated in prospective breast cancer clinical trials,”said Dr. Richard Pestell, director of the Kimmel Cancer Center at Thomas Jefferson University, and an author of the study. “However, we should start taking the breast tumor stroma into our clinical considerations sooner, rather than later.” The study appears in the May 1 online edition of American Journal of Pathology, together with another group’s study on stromal expression of caveolin-1 in breast cancer. A related study was published online in Cancer Biology & Therapy.

Gold Nanorods May Permit Heat Treatment of Tumors

Scientists at MIT, together with collaborators, have developed gold nanorods that can home in on tumors and then, by absorbing energy from near-infrared light and emitting it as heat, destroy the tumors with minimal side effects. The light heats the nanorods, but passes harmlessly through tissue. Although it has long been known that heat can kill tumor cells, it has previously been difficult to heat the tumor cells specifically while leaving the surrounding tissue undamaged. In designing the nanorods, the researchers took advantage of the fact that blood vessels located near tumors have tiny pores just large enough for the nanorods to enter. The team developed a polymer coating for the particles that allows them to survive in the bloodstream longer than any other gold nanoparticles. In experiments in mice with tumors, the nanorods were injected into the bloodstream and accumulated in the tumors. With near-infrared laser treatment, the tumors disappeared in 15 days. The treated mice survived for three months with no evidence of recurrence, until the end of the study, while mice that received no treatment or only the nanorods or laser, did not. The researches noted that the gold nanorods also have potential in the detection and diagnosis of tumors, because the particles can be imaged by a technique known as Raman scattering. This work was reported in two recent papers, one in Cancer Research and the other in Advanced Materials. [MIT release]

Syndicate content