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Unfolding Huntington’s Disease
Unfolding Huntington’s Disease
How Mutant Proteins Damage Nerve Cells

Jianning Wei, Ph.D. Photography by Paige Russo

By Rachel Plunkett

In Huntington’s disease, a single faulty gene gradually damages parts of the brain over time. After about 20 years, it’s fatal with no known cure. Jianning Wei, Ph.D., associate professor at FAU Charles E. Schmidt College of Medicine, said her research focuses on understanding how this disease progresses, which could provide insight for a cure.

Huntington’s happens when nerve cells in the brain break down over time, causing uncontrolled movements, depression, mood changes, and uncharacteristic anger. This defective gene codes the blueprint for a protein called Huntingtin.

As a person ages, proteins — which are important for every process within a cell — can fold incorrectly, causing them to become dysfunctional. Protein misfolding is believed to be the primary cause of most neurodegenerative diseases, and Wei is curious how these misfolded Huntingtin proteins interact with and possibly impair how other proteins perform in the body.

A misfolded protein can be thought of somewhat like the trash or waste within a cell that neurons need to get rid of, Wei explained. The buildup of these misfolded proteins can block pathways that are essential for cell function. “This is similar to a traffic jam,” Wei explains. “When you have a lot of cars backed up on a highway due

to a car accident, then the cars cannot get through. That’s what happens with the pathways between neurons with Huntington’s disease.”

Wei studies how the accumulation of misfolded proteins causes a chain reaction that allows Huntington’s disease to progress. “What we are thinking is that this mutant Huntingtin protein is interacting with different proteins that it is not supposed to interact with. This makes the cell more vulnerable to stress over time in comparison to a healthy cell,” Wei said.

To do this work, Wei analyzes the protein-to-protein interactions within the mutated Huntingtin cells, compared to healthy cells under both stressful and normal conditions. Through this, it’s possible to single out which protein is being altered by mutated Huntingtin, and what the role of that protein might be in a healthy cell compared to a diseased cell.

“Understanding what’s happening when these proteins interact with each other at the molecular level then allows us to figure out how these protein interactions impact the way a nerve cell functions,” she said. The idea is that these changes in the way proteins behave could cause the nerve cells to stop functioning and break down over time, which might lead to the symptoms experienced by patients with Huntington’s disease.

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