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2008 Grants - Thinakaran
Altering Microdomain Localization of Gamma-Secretase in Transgenic Mice
Gopal Thinakaran, Ph.D.
University of Chicago
2008 Investigator-Initiated Research Grant
Gamma-secretase is a key enzyme in the development of Alzheimer pathology. It performs the final step in the production of beta-amyloid by cutting beta-amyloid from its parent molecule. Beta-amyloid then goes on to aggregate into amyloid plaques, which are a characteristic feature of Alzheimer pathology. Gamma-secretase also produces other molecules that are important for the normal function of nerve cells.
Like most enzymes, gamma-secretase is localized to specific compartments (microdomains) within cells. Such localization affects the enzyme's function by restricting its access to include only proteins that are found in the same compartments. In the case of gamma-secretase, localization is achieved by the attachment of specific fatty acids to different components of the enzyme, thereby determining where those components reside within the cell.
Gopal Thinakaran, Ph.D., and colleagues are studying how localization of gamma-secretase within nerve cells affects the ability of those cells to produce beta-amyloid. They have preliminary evidence suggesting that the attachment of a specific fatty acid to gamma-secretase causes the enzyme to be localized to compartments where it produces beta-amyloid. They plan to further study this process.
The researchers will use genetic engineering techniques to produce mice that have a mutation that prohibits attachment of the fatty acid to one of the gamma-secretase components. They will then measure production of beta-amyloid in the brains of these mice, as well as the production of other molecules that require gamma-secretase activity in other compartments. These experiments may identify a way to reduce production of beta-amyloid without affecting the production of other important molecules.