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2008 Grants - Goodwin
Gamma-Secretase Inhibitors Induce Cell Cycle Defects and Chromosome Aneuploidy
Bonnie Goodwin, Ph.D.
University of South Florida
2008 New Investigator Research Grant
Gamma-secretase is a cluster of enzymes that has been a focus of research on the causes of Alzheimer's disease. The enzyme cluster plays a role in cutting amyloid precursor proteins (APP) into beta-amyloid fragments, key suspects in Alzheimer pathology. Furthermore, genetic defects in components of gamma-secretase, notably the protein presenilin-1 (PS1), have been linked to inherited forms of Alzheimer's disease. Thus, inhibition of gamma-secretase is a potential strategy for slowing the progression of Alzheimer's disease. However, gamma-secretase performs other important functions in cells.
Bonnie Goodwin, Ph.D., and colleagues are studying the role of gamma-secretase and the effects of gamma-secretase inhibitors in nerve cells and other cells. They have found that PS1 interacts with the cells' genetic material (chromosomes) and that inherited mutations in PS1 can lead to chromosomal abnormalities. These observations suggest that PS1 mutations associated with some forms of Alzheimer's disease may cause genetic abnormalities in cells that give rise to nerve cells.
Similar to PS1 mutations, inhibitors of the gamma-secretase complex (which contains PS1) caused genetic abnormalities in cells and affected the ability of the cells to divide normally. Some of these effects were dependent on the presence of APP. Dr. Goodwin and colleagues plan to further study the effects of gamma-secretase inhibitors, focusing on inhibitors that specifically inhibit the ability of the enzyme complex to cut APP. They will also study how APP and beta-amyloid influence the effects of gamma-secretase inhibitors. These studies may provide important insights into the potential use of gamma-secretase inhibitors for treatment of Alzheimer's disease.