How an Important Gene for Alzheimer’s Called MAPT is Turned On

Nick Cochran, PhD
HudsonAlpha Institute for Biotechnology (Huntsville, AL)

Mentors

Richard M. Myers, PhD
HudsonAlpha Institute for Biotechnology (Huntsville, AL)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$199,896
Grant Reference ID:
A2019129F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southern
Nick Cochran, PhD

Mechanisms of MAPT Regulation

Summary

We would like to find out how an Important Gene for Alzheimer’s disease called MAPT is turned on in neurons, the cells in your brain that control your thinking. This important gene MAPT is the instruction set for a protein called tau. 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.

Details

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.

About the Researcher

Dr. Nick Cochran obtained his undergraduate degree in chemical engineering and completed a senior honors thesis in the lab of Dr. Douglas Martin at Auburn University in 2010. Nick completed his PhD in neurobiology in the lab of Dr. Erik Roberson at UAB in 2015. He is currently a postdoctoral fellow in the lab of Dr. Richard Myers at the HudsonAlpha Institute for Biotechnology and investigates the human genetics and genomics of neurological diseases. In all of his research roles, Nick has contributed to research for Alzheimer’s disease and other neurodegenerative diseases.

Personal Story

I became interested in neuroscience and as an undergraduate. As I saw the devastating effects of neurodegenerative diseases ripple through both sides of my family, I pursued research opportunities to work towards understanding and treating neurologic diseases, with a special interest in neurodegenerative diseases. Because of this translational interest, my initial contributions to the field were in the areas of gene therapy and drug discovery. I became interested in genetics and genomics because during my time in graduate school, large GWAS studies and the first rare variant studies for Alzheimer's and other neurodegenerative diseases provided even more evidence to what we already knew from family-based linkage studies: understanding disease-associated genetics is a critical foundational step to understanding disease pathways that we may be able to target therapeutically. I am excited that, due to the support of BrightFocus donors, I will be able to contribute to understanding how MAPT, an important gene in many neurodegenerative diseases, is regulated.

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