Mechanisms of MAPT Regulation

Project Summary

I am working towards understanding how an important gene for Alzheimer’s called MAPT (which is the instruction set for a protein called tau) is turned on in neurons, the cells in your brain that control your thinking.

The first critical thing to know to understand how a gene is turned on is to figure out what interacting elements makes physical contact with the main on switch (called the "promoter") for that gene. Interacting elements can be either proteins (called "transcription factors") or stretches of DNA that can help transcription factors bind (called "enhancers"). Knowing the enhancers that interact with the promoter can help us understand what transcription factors are close to the promoter, so I will first measure what stretches of DNA are physically interacting with the promoter of MAPT, which would make these stretches of DNA candidate enhancers. The next step for understanding if these candidate enhancers help turn tau on is to test, individually, the effect of each of these candidate enhancers on how much tau is produced. I will test this both by testing how much expression-inducing activity each candidate enhancer has when tested in an isolated setting, and by testing the effect of blocking the function of the candidate enhancers on tau expression directly.

By performing these experiments in different types of neurons, where tau is highly expressed, and performing the same experiments in precursor cells that are a lot like neurons, but are not fully mature and do not express much tau, I will be able to get a clear picture of what signals are clearly associated with tau expression by checking for signals that are present in neurons (where tau is highly expressed), but not in precursor cells (where tau is barely expressed). Furthermore, analyzing the very specific data collected here along with other types of more general data that we already have collected on signals associated with expression near MAPT will lead to a much better understanding of how MAPT is turned on in neurons.

Understanding how MAPT is turned on to produce tau is important because tau causes problems in Alzheimer’s disease, and scientists think that reducing tau might be helpful as a treatment. If we can figure out how MAPT is turned on in neurons, it might help us know how we could turn it off, which would reduce tau and might help people with Alzheimer’s disease.