Meet Dr. April Darling, an APDA-funded researcher studying methods to reduce alpha-synuclein in the brains of people with Parkinson’s disease.

Our A Closer Look blog is designed to educate, inform, and inspire you through a variety of topics and insights about Parkinson’s disease (PD). One way we do that is through our Interview with APDA Researchers series, as a part of our Parkinson’s Research collection, to give you a closer look at some of the dedicated APDA-funded researchers who are working tirelessly to understand this disease.

Today we introduce you to Dr. April Darling, a post-doctoral fellow at University of Pennsylvania School of Medicine. She is the recipient of a 2020-2021 APDA post-doctoral fellowship and is currently studying ways to prevent accumulation of alpha-synuclein in the brain, which is thought to play a large role in the development of Parkinson’s disease (PD). We asked her questions about her work.

Q: What is the overarching goal of your research on alpha-synuclein accumulation? What do you hope to find out?

A: One of the main characteristics shared by all neurodegenerative diseases, including Parkinson’s disease (PD), is the accumulation of aggregated proteins in the brain of patients. In PD, the problematic aggregating protein is called alpha-synuclein and appears in structures termed Lewy bodies. In animal PD models, elimination of alpha-synuclein aggregates leads to a reduction in disease symptoms and severity. Helpful proteins termed chaperone proteins are one of the cells natural ways of getting rid of these aggregated proteins. However, in disease, the chaperone proteins are not able to overcome the burden of protein aggregation and accumulation, and cellular processes go awry which we think leads to development of disease. Therefore, we want to engineer these chaperone proteins to be better at their job with the goal of making them so that they can effectively and efficiently get rid of aggregated proteins such as pathological alpha-synuclein in the brain of patients in PD. We want to see if these engineered proteins, that can efficiently rid the cell of accumulated alpha-synuclein, will be effective as a therapeutic for disease treatment.

Q: Could you describe how you perform your studies?

A:  In order to identify proteins that can rescue the toxic effects of alpha-synuclein aggregation and accumulation, we start by using a very simple yeast system. Similar to humans, yeast are sensitive to the accumulation of alpha-synuclein and it leads to a decrease in their growth rate and ultimately cell death. We can rescue this reduced growth with certain chaperone proteins called protein disaggregases which have the ability to detangle aggregated proteins such as alpha-synuclein. We use this yeast system to screen all of our engineered chaperone proteins in an attempt to discern the ones that are more effective than the wild-type protein disaggregases.

Once we identify the most promising proteins, we directly study their ability to prevent and reverse aggregation of alpha-synuclein. If our engineered chaperone proteins can effectively reverse the aggregation of alpha-synuclein, we then test them in brain cells or neurons to see if they can prevent disease pathology. If they are effective in this system, we then move on and test them in an animal model that replicates the key features of PD.

Q: Can you tell us a little bit about what you have found out so far?

A:  So far, we have excitingly shown that some mutants of our engineered chaperone protein TRIM11 are better at rescuing alpha-synuclein toxicity as compared to the wild-type TRIM11 protein in yeast. Looking under the microscope, we have demonstrated that they do this by preventing and/or reversing the aggregation of alpha-synuclein in the cells. Next, we will purify the mutant protein of interest and test them against alpha-synuclein to see if they can prevent and/or reverse its aggregation.

Q: What fuels your passion for research?

A:  I have always loved science and have been researching and gathering data on different topics since I was a kid. I knew that I wanted to go into medical research at an early age, and after my grandfather passed away from Parkinson’s disease, I decided that I wanted to study neurodegenerative diseases in order to try to find better diagnostics and treatment for those challenged by the disease. Since then, I have stuck with my goals of researching these complex diseases, but medical research is difficult and sometimes I have to step back and remind myself what drives my passion for this work. I want to be able to give those affected with PD hope and comfort. I want them to find hope in the possibility that we may discover more effective treatments for the disease and I want them to find comfort in the fact that medical researchers are fastidiously working on the problem every single day and trying to come up with better solutions.

Tips and Takeaways

• April Darling, an APDA-funded researcher is studying ways to decrease alpha-synuclein aggregation in nerve cells. This aggregation is thought to be responsible for development of PD.
• If her research is successful, it would be an important step towards understanding how to reduce aggregation of alpha-synuclein. This could lead to a new therapy that delays or prevents disease progression, like these potential therapies which are currently in clinical trial.
• We are only able to fund this research because we receive donations from dedicated people like you. If you would like to support critical work like this, please consider making a donation