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2006 Grant - LeVine
Chaperone-Mediated Protein Refolding Dysfunction in Alzheimer's Disease
Harry LeVine III, Ph.D.
University of Kentucky Research Foundation
2006 Investigator-Initiated Research Grant
The 30,000 or so proteins that are found in the human body must each assume a specific three-dimensional shape in order to carry out their specialized function. But sometimes proteins do not "fold" properly when they are being made, and sometimes they can become "misfolded" even after they have assumed the correct shape. Ordinarily, there are mechanisms within each cell to take care of misfolded proteins. Occasionally, however, a protein may be irreversibly misfolded. Such irreversible processes are thought to be important in the pathology of many neurodegenerative disorders, including Alzheimer's disease.
The identification of two misfolded proteins in Alzheimer's disease-the small protein fragment beta-amyloid and the larger protein tau-has led many researchers to believe that the mechanism for ensuring proper protein folding has gone awry in Alzheimer's disease. In this regard, some researchers believe that poor "chaperone" activity may be key to the disease process. Chaperones are a group of proteins that help other proteins assume their correct shape.
Harry LeVine III, Ph.D., and colleagues plan to investigate the relationship between Alzheimer's and chaperone activity. They plan to measure the chaperone and refolding activity in brain extracts taken from mice that have been manipulated to have an Alzheimer-like pathology. They also plan to determine how protein folding and refolding capabilities in human brain change during the course of the disease.
Preliminary work suggests that a particular type of chaperone called heat shock protein 70 may be crucial to prevent misfolding of beta-amyloid. Further work will help scientists understand the complexity of protein folding in the context of Alzheimer's disease and may lead to ways to prevent the formation of toxic proteins in the brain.