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2017 Grants - D'Onofrio
Role of Polyubiquitination in Alzheimer's Disease
Mariapina D'Onofrio, Ph.D., M.D.
University of Verona
2017 Alzheimer's Association Research Grant (AARG)
How does modification of tau affect the formation of tau tangles?
One of the characteristic features of Alzheimer's disease in the brain is the presence of tau tangles, which are abnormal accumulations of the protein tau. In healthy cells, tau functions as part of the cell structure and helps the cell transport nutrients. Scientists have been studying why tau becomes abnormal and forms tau tangles in an effort to understand the causes of Alzheimer's disease.
Another common protein in the cell is ubiquitin. Ubiquitin is a small protein that is attached to other "old" proteins, marking them for degradation. In most situations, a protein marked with ubiquitin would be broken down by the cell. Recently, however, scientists have observed that some of the tau contained in tau tangles is marked with long chains of ubiquitin (polyubiquitin). This finding suggests that the marking of tau with polyubiquitin may trigger the formation of tau tangles.
Mariapina D'Onofrio, Ph.D., M.D., and colleagues have proposed a series of studies to explore what happens when tau is marked with polyubiquitin. The researchers will use chemical and biochemical methods to attach polyubiquitin to different parts of the tau molecule, and then observe how that modification affects the ability of tau to form tau tangles. They will also study how polyubiquitin affects the ability of cells to dispose of old copies of tau. Dr. D'Onofrio and colleagues will conduct initial experiments in test tubes to control conditions, but then repeat them in living cells.
Dr. D'Onofrio's team will also explore manipulating cellular pathways that remove polyubiquitin from proteins, They will study how this process affects the ability of cells to dispose of old copies of tau.
This research project will explore the biochemical mechanisms involved in one of the fundamental processes in Alzheimer's disease, the formation of tau tangles. The results may help scientists identify ways to stop the formation of these abnormal structures and enhance degradation, which could possibly disrupt progression of the disease.