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RESEARCH BRIEFS
Why Familiar Drug Gives Surprising Hope Against Diabetic RetinopathyDiabetic retinopathy is a leading cause of blindness in the U.S., and for the 20,000 sufferers who are likely to become blind each year, new hope for prevention may be just around the corner—it's called aspirin.
A section from the retinal capillary network of a diabetic patient shows colocalization of dense deposits of factor XIII (left) and GPIIIa (right). Both proteins are thought to be involved in formation of microthrombi. Courtesy of Mara Lorenzi This form of retinopathy has long been suspected of being the result of microthrombi, tiny blood clots in the capillaries of the eye that lead to blockages in blood circulation which, in turn, result in tissue damage and eventually cell death. Work reported in the June Diabetes by researchers at Schepens Eye Research Institute lends considerable support to this hypothesis. Mara Lorenzi, HMS associate professor of ophthalmology, together with Daria Boeri and Michele Maiello, visiting scientists from the University of Genoa (Italy), have carried out postmortem examinations on the retinas of diabetic patients and nondiabetic controls. The researchers teased away the intact capillary network from the donated retinas and then tested them for the presence of factor XIII and the glycoprotein GPIIIa, both known to play key roles in the blood clotting and platelet aggregation that leads to thrombosis. They found that the number of capillaries in which the proteins colocalized and the capillary area occupied by microthrombi were two- and four-fold higher, respectively, in samples from diabetic patients. Furthermore, in diabetic retinas apoptosis was more likely to be observed in proximity to sites of microthrombosis, suggesting a direct link between capillary blockage and cell death. This work provides an explanation for previous reports that aspirin could increase retinal blood flow in diabetic patients and suggests that the benefits of aspirin for these sufferers should be closely examined.
Fly Model of Alzheimer's Starts Untangling DiseaseRecent advances in Alzheimer's research have implicated several proteins in the pathology of this debilitating disease. One of them, the microtubule-binding tau, is known to undergo dramatic conformational changes leading to the formation of neurofibrillary tangles, dense aggregates of abnormal protein that pack the cell cytoplasm and compromise neuronal function. At first glance these aggregates would seem to provide an etiology for the disease; however, the age-old question of cause and effect remains: do these aggregates contribute to the development of Alzheimer's or are they just a symptom? A report in the June 15 Science suggests the latter. A team led by Mel Feany, HMS assistant professor of pathology at Brigham and Women's Hospital, has expressed human tau in Drosophila. The genetically altered flies developed normally, but adults died prematurely showing evidence of tau accumulation and neuronal degeneration. Aging was accompanied by changes in tau that made it indistinguishable from the abnormal tau found in human dementia. In addition, flies transfected with a mutant version of tau, associated with human early-onset dementia, had more severe symptoms and even shorter life spans. But none of the transfected flies showed any signs of neurofibrillary tangles. The implications of this study are fundamental. The neurofibrillary tangles seen in human dementia may be just a secondary effect. The real damage, protein modification, may occur well before structural abnormalities are apparent. But there is a caveat: fly models of human disease have obvious limitations, including in this instance a considerable loss of neurons not usually seen in human neurodegenerative disease. Nevertheless, the power of Drosophila genetics can now be mobilized to tackle the molecular biology underlying tau toxicity.
Shifty Cell Cycle Regulator UncoveredAlthough it is well known that regulation of the eukaryotic cell cycle is based on a multitude of transcriptional and posttranslational events, recent evidence suggests that an entirely different phenomenon, isomerization of prolyl peptide bonds, may also contribute to the checks and balances of cell division. Proline is unique among the amino acids since its cyclical nature ensures that it exists as either of two conformations, cis or trans. Conversion between these two isomers can result in dramatic changes in the conformation of proteins with profound consequences. The small peptidyl-prolyl isomerase, Pin1, for example, has been shown to be essential for mitosis in mammalian cells. However, though Pin1 is known to bind to many cell cycle players, a cell cycle requirement for isomerase activity per se has yet to be conclusively demonstrated. Todd Stukenberg, of the University of Virginia Medical School, and Marc Kirschner, the Carl W. Walter professor of cell biology and head of that department at HMS, have addressed this issue in May's Molecular Cell. They have shown that the properties of one of the potential targets for Pin1, the cell division–cycle phosphatase Cdc25, can be altered in a manner that is best explained by prolyl isomerization. Germane to their argument is that modification of Cdc25 occurs when it is incubated with relatively miniscule amounts of Pin1. Under these conditions, which preclude the quantitative formation of a Cdc25–Pin1 complex, changes in the conformation and activity of Cdc25 were observed. Conformational changes were evident by altered protease digestion patterns and greatly increased affinity for the monoclonal antibody MPM-2. Depending on the prior phosphorylation status of Cdc25, catalytic amounts of Pin1 elicited increases or decreases in its phosphatase activity. The findings should encourage others working in the field since in the absence of high-resolution structural data, prolyl isomerization has been notoriously difficult to prove. —Briefs by Tom Fagan
To Come in Focus:In the July 1 Journal of Clinical Investigation, HMS researchers Shinichiro Ryu, Denise Faustman, and colleagues report that they were able to permanently reverse established Type I diabetes in a mouse model. A full discussion of the new findings will appear in the July 13 Focus. |
