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2006 Grant - Sisodia
Purification and Structural Analysis of the Presenilin 1/Gamma-Secretase Complex
Sangram S. Sisodia, Ph.D.
University of Chicago
2006 Investigator-Initiated Research Grant
A small protein fragment called beta-amyloid has long been suspected as a culprit in Alzheimer's disease pathology. Many scientists believe that certain beta-amyloid-based structures are highly toxic to neurons and may kick-start the disease. For this reason, much research has focused on why beta-amyloid accumulates in the brain.
Beta-amyloid is clipped from a much larger protein by an enzyme complex called gamma-secretase. This complex contains at least four different proteins, of which one, presenilin, harbors the activity that is responsible for releasing beta-amyloid. Because of the pivotal role of gamma-secretase in Alzheimer's, many researchers have tried to study its properties in great depth. However, the entire complex has proven notoriously difficult to purify and analyze.
Sangram Sisodia, Ph.D., and colleagues have proposed to purify the complex using highly sophisticated and novel methods. One of the main problems scientists have to deal with in isolating gamma-secretase is that its normal environment is the cell membrane. Proteins embedded in the cell membrane must be removed with detergents, a process that usually destabilizes large complexes, causing them to fall apart.
Dr. Sisodia's team will stabilize the complex using specially developed antibodies that bind very tightly to the complex, allowing it to be removed from the cell membrane intact. Once the researchers have purified enough of the complex, they will make protein crystals, which can be used to uncover the three-dimensional structure of gamma-secretase. Knowing how the complex is put together should help researchers figure out how it works. This study may facilitate the development of novel therapeutics that can inhibit secretases and prevent production of beta-amyloid.