Utilizing a Molecular Switch to Correct Disruptive Parkinson's Disease Protein Clumps
Research has shown that a protein called alpha-synuclein is likely a key driver of Parkinson’s disease (PD) progression. If the regulation of alpha-synuclein is out of balance in the brain, it can cause major stress to neurons and lead to their breakdown, a hallmark sign of PD. While most studies have focused on how alpha-synuclein goes haywire in PD, Jane Aldrich, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, is taking a different approach: she will be investigating how to improve the neurons’ ability to regulate alpha-synuclein and thereby stop cellular damage.
Proteins are used to perform the tasks and processes that keep everything running smoothly inside cells. Some proteins, like alpha-synuclein, are chemically modified in the cell by attaching a small group at specific locations which can change their behavior. In PD, when alpha-synuclein is modified it forms toxic threads in neurons, which eventually form clumps. There is a separate protein, called PP2A, whose job is to take the chemical group off alpha-synuclein. However, in many PD cases, this protein doesn’t work properly, potentially leading to the accumulation of clumped, chemically modified alpha-synuclein protein.
In her lab at the University of Florida, Dr. Aldrich has identified a small molecule that can repair PP2A in cells. A functioning PP2A can restore the regulation of alpha-synuclein, preventing PD-associated damage. In collaboration with Dr. Paramita Chakrabarty, Dr. Aldrich will use a mouse model of alpha-synuclein dysregulation and inject the mice with this small molecule that can potentially restore the function of PP2A. After treating mice for up to two months, they will look at brain tissue samples under a microscope to see if this molecule was able to prevent alpha-synuclein from clumping inside neurons.
Next, Dr. Aldrich will test variations of the PP2A repair molecule, looking for versions that might work better than the original. As with all new drugs or treatments, even slight molecular changes can lead to improved function and outcomes. By doing these experiments, Dr. Aldrich hopes to find better PP2A repair molecules and advance these compounds for potential future therapeutic use.
When asked about what this award and support means to her, Dr. Aldrich replied, “I am very excited that research from my lab could possibly help identify disease-modifying therapies for Parkinson’s disease. I have a long-standing interest in exploring compounds that are active in the brain, and this will be the first opportunity for my lab to expand our research to target a neurodegenerative disease. The proposed research will provide proof of concept that compounds we synthesize can modulate the state of alpha-synuclein in PD models and have potential application as treatments for the disease.”
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