How are Phosphates Removed from Tau?

We will characterize the complex of Hsp70-PP5 that removes phospho groups from tau. We will use structural biology methods to explore the structure of the Hsp70-PP5 structure and its interactions with tau. In addition, we will use chemical biology approaches to map the protein-protein interactions between Hsp70 and PP5, towards building molecules that might promote this interaction.

The accumulation of the protein, tau, in the brain is closely associated with neuron loss and dementia in Alzheimer’s disease (AD) patients. In AD patients, tau is abnormally modified by phosphorylations and recent findings have shown that phosphorylations at specific sites on tau may proceed disease. While the enzymes that add phosphorylation groups are well-known, there has been significantly less attention paid to the enzymes, termed phosphatases, that remove these modifications. In exciting preliminary results, we found that specific proteins, termed chaperones, which are abundant in the brains of healthy patients, bind to tau and seem to recruit a specific phosphatase, PP5. We hypothesize that the interaction of chaperones with PP5 may be important in removing phosphorylations from tau and protecting the brain from AD. In the proposed research, we will probe this important question, using cutting-edge, scientific techniques. This work is expected to uncover key events in the early stages of AD, potentially revealing new therapeutic targets.

While there has been extensive work to understand how tau is hyper-phosphorylated in AD, less attention has been spent on exploring the mechanisms of de-phosphorylation. Because tau modification is a balance of these two processes, we seek to develop a structural and mechanistic understanding of the de-phosphorylation process.

By better understanding the mechanisms of tau de-phosphorylation, we hope to uncover new drug targets or opportunities for promoting this activity.