Researchers carry out in-depth characterization of a major gene involved in neurodegenerative diseases

Within our brain cells, there is a road network of tubular structures called microtubules. They give cell structure and help transport nutrients and other important substances from one part of the nerve cells to another. Tau is an important protein that normally binds to these microtubules.

Abnormalities in tau protein are associated with many brain diseases, including Alzheimer’s disease. In Alzheimer’s disease, tau proteins change shape, stick to each other and no longer bind to microtubules. This aberrant tau disrupts the function and communication of neurons and other brain cells, causing some of the symptoms of Alzheimer’s disease.

Several studies indicate that reducing tau levels prevents classic damage induced by aberrant tau protein. Nick Cochran, Ph.D., a research scholar at the HudsonAlpha Institute for Biotechnology, and his lab are working to understand Tau and its expression at a deeper level in hopes of discovering what’s going wrong and how to better understand it. prevent or reverse it.

“The more we learn about the human genome, the more genetic elements involved in healthy and diseased states emerge,” Cochran says. “Coding genetic variation is no longer the sole focus of understanding the role of genetics in disease pathology.

“Stretches of DNA called cis-regulatory elements, along with transcription factors and other elements that together are responsible for turning genes on and off, have major implications for human diseases. Dive in gene regulation will lead to a more holistic picture of how variation in our genomes drives disease risk, allowing us to better understand and target the problem involved in these diseases.

In a new study published in The American Journal of Human GeneticsCochran and his team, along with the Myers lab at HudsonAlpha, used numerous genomic technologies to better understand MAPT expression and identify novel regulatory regions that could one day be targets for therapeutic treatments.

“This represents a very in-depth analysis of MAPT expression,” says Bri Rogers, Ph.D., postdoctoral fellow and first author of the study. “We started by coupling gene expression and DNA accessibility data at the cellular level with neurons and brain tissue in culture. Once we identified interesting potential regulatory elements, we used numerous orthogonal approaches to confirm that they regulated MAPT expression.”

Through these comprehensive studies, the team identified 97 candidate regulatory elements that control MAPT expression. They primarily focused on the noncoding cis-regulatory elements that regulate MAPT, some proximally and some distantly. Using CRISPRi, the researchers confirmed whether the named elements regulated MAPT.

“These results are exciting because many of the elements we found are so distant from MAPT that variants within these regulatory regions would not have been associated with MAPT before,” says Rogers. “Linking these regulatory elements to MAPT really helped us understand the potential consequences of variants in these regions. »

The team also identified interesting rare variants in some MAPT regulatory elements, but these rare variants appear to act in a protective rather than deleterious manner. The variants are present in people who do not have Alzheimer’s disease and are depleted in those with Alzheimer’s disease. Cochran and his team hypothesize that these variants damage the enhancer element, thereby reducing MAPT expression and protecting against neurodegenerative diseases.

“It is important to note that rare genetic variants can be both deleterious and protective with respect to their effect on disease risk. Although it is still early to analyze the effects of rare non-coding variants on risk illness, it is likely that this is the case.” “This is the first of many discoveries in which this category of genetic variation will prove important,” says Cochran.

This study provides insight into how genetic variants around MAPT contribute to disease risk. By identifying transcription factors that bind to regulatory regions, future studies may reveal new therapeutic targets for Alzheimer’s disease and other tauopathies.