Fruit flies yield clues to clinical heterogeneity of early-onset Alzheimer's diseaseSequencing of the genome of the fruit fly Drosophila revealed five years ago that ~60% of genes associated with known human diseases are also present in the fly genome, and in accordance with this finding, modeling of human genetic diseases in Drosophila has become a commonly used approach for understanding the causes and molecular mechanisms of human disease. In work reported this week, researchers have now extended this approach by showing that the fly can also be used to investigate the variation seen within a human disease--in this case, Alzheimer's disease--and the factors responsible for such variation.
The findings are reported in the May 23rd issue of Current Biology by Mark Fortini and colleagues at the National Institutes of Health.
Early-onset familial Alzheimer's disease is an aggressive, inherited form of Alzheimer's disease that can be caused by mutations in a gene named Presenilin. Over 130 different mutations in Presenilin result in a wide range of disease severity, with ages of onset from just 24 years to 65 years of age. In the new work, researchers created transgenic flies expressing mutant versions of the Presenilin gene; fourteen different mutations were used, representing the broad range of effects seen in Alzheimer's disease. By developing an array of genetic, molecular, and biochemical assays for Presenilin function, the researchers were able to demonstrate that the severity of the mutations in human patients correlated with a gradation of Presenilin activity when these mutant versions of the Presenilin gene were expressed in files.
The linkage of Presenilin mutant activities in Drosophila with their age of onset values in humans has important implications for the ongoing debate about the role of Presenilin mutations--as opposed to additional genetic or environmental influences--on the severity of early-onset Alzheimer's disease. The new study supports the view that the clinical heterogeneity associated with this genetic disease is primarily due to the different mutations affecting Presenilin activity itself. Moreover, the study again illustrates that insights into the underlying mechanisms of human disease can be gained by studying the relevant genes and mutations in genetic model organisms such as flies, worms, and mice. With this approach, many of the confounding factors seen in human families, such as geographical and ethnic differences, as well as small numbers of affected individuals, can be avoided. This latest study raises the hope that perhaps there will be new uses for the fly in untangling the complicated web of human disease.
The researchers include Glen A. Seidner of SAIC-Frederick, Inc., National Institutes of Health in Frederick, MD and the University of Pennsylvania School of Medicine in Philadelphia, PA; Yihong Ye of NIDDK, National Institutes of Health in Bethesda, MD and the University of Pennsylvania School of Medicine in Philadelphia, PA; Martha M. Faraday and W. Gregory Alvord of NCI-Frederick, National Institutes of Health in Frederick, MD; Mark E. Fortini of NCI-Frederick, National Institutes of Health in Frederick, MD and the University of Pennsylvania School of Medicine in Philadelphia, PA.
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and with Federal funds under DHHS#NO1-CO-12400. Support was also provided by NIH grant AG14583 from the National Institute on Aging.
Seidner et al.: "Modeling Clinically Heterogeneous Presenilin Mutations with Transgenic Drosophila." Current Biology 16, 1026–1033, May 23, 2006. DOI 10.1016/j.cub.2006.04.004. www.current-biology.com
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