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2010 Grants - Zhou
Regulation of Tau Phosphorylation in Neurons by Par3/6 via GSK-3s
Fengquan Zhou, Ph.D.
Johns Hopkins University School of Medicine
2010 New Investigator Research Grant
Tau is a protein that normally functions to maintain nerve cell structure and aid in transport of nutrients throughout the cell. In persons with Alzheimer's disease, tau becomes abnormally modified by the addition of phosphate chemical groups (phosphorylation). This change leads to the formation of neurofibrillary tangles, one of the hallmark features of Alzheimer pathology. The pathways leading to abnormal phosphorylation of tau are not well understood.
Fengquan Zhou, Ph.D., and colleagues are studying an enzyme known as glycogen synthase kinase-3 (GSK-3), which phosphorylates tau. Consistent with other researchers, they have found that GSK-3 is normally active in cells, but its activity can be reduced by several signaling pathways. Dr. Zhou's team found that one such pathway involves another set of proteins known as Par3/6. When Par6 activity was reduced, the activity of GSK-3 was increased, leading to an increase in the phosphorylation of tau.
Dr. Zhou and colleagues plan to extend their studies to examine the role of Par3/6 in the development of neurofibrillary tangles. They will use mice that have been genetically altered to express high levels of GSK-3 to determine if Par3/6 regulates the activity of GSK-3. The researchers will also determine if Par3/6 activity is part of a signaling pathway activated by known signals, such as growth factors. Finally, Dr. Zhou's team will perform biochemical studies to examine the molecular mechanism by which Par3/6 regulates GSK-3. These studies will advance our understanding of a key step in Alzheimer pathogenesis, and may identify potential targets for the development of new drug therapies.