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How do proteins that help protect DNA ensure genes are read properly during Alzheimer’s disease?
Matthias Truttmann, Ph.D.
University of Michigan
Ann Arbor, MI - United States
Background
A person’s DNA is tightly packaged inside their cells. Specific proteins open up the portions of DNA containing genes as needed. This is carefully controlled in part by special proteins (called enzymes) attaching a small molecule called AMP to the proteins—a process called “AMPylation.” As a person ages, many regulatory systems inside cells become less effective. This could be true for AMPylation, which could place a person’s DNA at risk of improper use or damage.
Recent studies have found unusually high levels of enzymes that perform AMPylation inside brain cells in people who had Alzheimer’s disease. Too much AMP addition to proteins could change how they are able to safeguard brain cell DNA. Dr. Matthias Truttman will study if this may be one way genes become dysregulated during Alzheimer’s disease.
Research Plan
Dr. Truttman’s team will examine how AMPylation changes the way DNA is packaged and controlled inside brain cells during Alzheimer’s disease. They will test whether AMPylation directly alters the function of proteins that help open and close the DNA.
First, the researchers will analyze brain tissue samples from people who had Alzheimer’s disease to determine if AMPylation is malfunctioning. Then, Dr. Truttman will work out the mechanistic basis of this process in small worms (called C. elegans). By using fluorescent chemical compounds attached to AMP, Dr. Truttman will be able to track how it interacts with proteins that protect DNA. Finally, Dr. Truttman will explore how the AMPylation of proteins alters functionality of the cell that helps “read” DNA. The ultimate goal of the work is to understand how changes in AMPylation can alter the way genes are turned on and off during Alzheimer’s disease.
Impact
This work could reveal ways in which AMPylation is beneficial, and how the process could be a potential target for therapy to ensure genes are properly turned on and off during Alzheimer’s disease.
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