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RESEARCH BRIEFS
No Home Run, But Batter on Base Against Lou Gehrig's DiseaseResearchers led by Robert Friedlander, HMS assistant professor of surgery at Brigham and Women's Hospital, report in the April 14 Science that blocking cell death enzymes prolongs the life of mice with amyotrophic lateral sclerosis (ALS), the motor neuron disease that killed the New York Yankees star Lou Gehrig. The finding extends previous work suggesting that inhibiting the proteases—called caspases—that orchestrate a cell's slow deterioration toward suicide could become part of a treatment for stroke, Huntington's disease, and traumatic brain injury. The molecular pathogenesis of most neurodegenerative diseases remains unclear. Yet no matter what the original cause, all those diseases have caspase activation in common, says Friedlander, suggesting that suppressing these enzymes may slow the conditions' course.
The motor neurons expressing activated caspase-1 (black dots) in the spinal cord of this mouse with ALS are doomed to die. In this study, the researchers implanted tiny osmotic pumps under the skin of transgenic mice that express a mutant SOD1 gene. These mice develop symptoms of ALS at around 90 days of age and die about 35 days later. The pumps delivered a tripeptide caspase inhibitor to the mice's cerebral ventricle, from where it spread down the spinal column. The treated mice showed the first symptoms 20 days later, remained stronger, and lived on average 26 days longer than did untreated mice. This amounts to a 70 percent increase in life span after disease onset, compared with 30 percent achieved by riluzole, the only FDA-approved treatment to date, writes Mark Gurney of Pharmacia Corp. in an accompanying article. Gurney developed the mouse model used in this study. The drug used here, however, is toxic in dogs when used in high doses, says Friedlander, so scientists will have to improve it or find a better one. The study also detected expression of caspase-1 and caspase-3 in the spinal cord of the mice even before symptoms appeared, addressing a concern that interfering with apoptosis may not help patients because it occurs swiftly only at the end stage of disease. This is not true, says Friedlander. Instead, he thinks that some caspases make a neuron sick long before it dies, providing ample time for intervention. "The data speaks for itself," he says. Study Makes Sweet Discovery of Bitter Taste ReceptorsMaking a significant contribution to understanding the biology of taste, HMS researchers report in the April 6 Nature their discovery of a family of candidate bitter taste receptors. The study was led by Linda Buck, a Howard Hughes Medical Institute investigator and HMS associate professor of neurobiology. Buck and coworkers used the Human Genome Project database to search for genes that encode taste receptors, ultimately homing in on genes that are likely to be involved in detecting bitter tastes. Other tastes perceived by mammals include sweet, salty, and sour.
A new group of bitter taste receptors, belonging to the G protein-coupled receptor superfamily, are expressed in cells receptive to taste (purple) in the tongue. In devising a strategy, they reasoned that the genes should be found at chromosomal locations previously implicated in bitter taste perception in mouse and human genetic studies. They also believed the taste receptors would be encoded by a group of related genes. Since previous studies had suggested the involvement of G proteins in bitter and sweet taste, the researchers specifically looked for new receptors belonging to the G protein-coupled receptor (GPCR) superfamily. The search turned up a group of candidate taste receptors in this family that are specifically expressed in cells receptive to taste. The newly discovered receptors are likely to be involved in tasting bitter substances, since a cluster of these genes was located at a human genomic locus corresponding to the SOA locus in mice—a region that controls the ability to taste sucrose octaacetate, a bitter compound. Another member of the family was found at a different chromosomal location involved in the ability of humans to taste the bitter chemical 6-n-propyl-2-thiouracil. In all, the researchers identified 11 genes with diverse sequences, which the researchers say is consistent with an ability to detect numerous bitter chemicals with a variety of structures. Indeed, a team of scientists at the University of California, San Diego, and the NIH, who reported the same receptor family in the March 17 Cell, found that several family members recognize bitter chemicals. Other contributors to the study were Hiroaki Matsunami and Jean-Pierre Montmayeur, HMS research fellows in Buck's laboratory. —This and briefs below by Lorene Leiter Mutation Bias Maintains Length Of Genetic RepeatsFound throughout eukaryotic chromosomes, most often in noncoding regions, are stretches of repeating DNA sequences known as microsatellites. Their function is still a mystery, but one of their features has puzzled biologists. Although the length of repeating units varies in any individual, the frequency with which certain lengths are found follows a bell-shaped distribution curve in humans and other primates. Certain mean lengths are common while very short or long lengths are uncommon. What makes this feature especially curious is the high mutation rate of microsatellites. With mutations usually involving the substitution or deletion of repeating units, one would expect a higher degree of variation in their length. Now a group of HSPH geneticists has discovered a mechanism that would account for the selection of certain microsatellite lengths. After studying the mutation in 337 families, research fellow Xin Xu and colleagues, working in the laboratory of Xiping Xu, HSPH associate professor and program director in population genetics, found a pattern in groups of four nucleotide–repeat microsatellites. The rate of "contraction" mutations—those causing the deletion of repeating units—increased exponentially with the size of the microsatellite. However, the rate of "expansion" mutations, causing the addition of units, was constant. The end result of such a phenomenon, say the researchers, would be the maintenance of a certain "critical repeat length," biasing mutations toward expansion when microsatellite length is short and contraction as the length grows. The study appears in the April Nature Genetics. MRI May Predict Alzheimer's DiseaseStructural magnetic resonance imaging (MRI) could become an important tool for diagnosing Alzheimer's disease in its very early stages, according to a report in the April 2000 Annals of Neurology. In the study, this technique was used to measure the volume of regions in the brain affected by the disease before the onset of clinical symptoms. Certain changes were predictive of Alzheimer's. Methods to diagnose the disease early are in demand since many new treatments on the horizon may slow its progression before it becomes debilitating. Currently, there is no way to determine whether a person with mild memory loss has entered the beginning stages of Alzheimer's. The study, funded by the National Institute on Aging, was conducted by Marilyn Albert, HMS professor of psychology at Massachusetts General Hospital, and her colleagues at MGH, Brigham and Women's Hospital, Boston University, and Brandeis University. Baseline MRI brain scans were performed on 119 participants, aged 65 years or older. Some had mild memory difficulties, but none had clinical symptoms of Alzheimer's. The researchers measured certain regions of the medial temporal lobe. Three years later, many people in the study developed Alzheimer's. After examining the MRI measurements, the researchers discovered that those who developed the disease had smaller volumes in certain regions initially, probably due to a loss of neurons. These included the entorhinal cortex and the superior temporal sulcus—both involved in memory—and the anterior cingulate, which affects executive functions such as organizing and planning. The MRIs were 93 percent accurate in distinguishing between people who were normal and those who initially had memory impairments and later developed the disease. They were 100 percent accurate in generally distinguishing between normal and Alzheimer's brains. Albert says that more research is needed before MRIs can be used in everyday practice as a diagnostic tool for Alzheimer's, but she says the study will help point scientists in the right direction about which areas in the brain to measure. |
