Research Department: Center for Alzheimer’s and Neurodegenerative Diseases Graduation Date: May 2019
Abstract: Tauopathies, such as Alzheimer’s Disease, belong to a class of progressive neurodegenerative disorders characterized by the prion-like aggregation of tau proteins. The prion hypothesis explains that misfolded proteins can corrupt native monomers into abnormal aggregates. The aggregates can then be transferred to other cells and amplified, causing the spread of insoluble protein. After uptake of a misfolded protein there is the potential for seeding, the conversion of naïve cellular protein into a pathogenic form. Proteolytic cleavage by proteases can potentially enhance this process by generating a pathogenic fragment that is more likely to seed. We hypothesized that inhibiting these proteases in the lysosome would decrease the release of these pathogenic fragments and decrease seeding. The general aspartyl protease inhibitor pepstatin, when bound to the cell- penetrating peptide penetratin, was found to decrease tau seeding. This inhibitor complex was also found to decrease tau uptake, suggesting that seeding was decreased due to lower tau entry into the cell. While initially thought to be caused by protease inhibition, it was next determined that the decrease in tau uptake was caused by pepstatin-penetratin binding to the tau fibrils. Later experiments, however, revealed that the binding was actually due to pepstatin-penetratin’s interaction with heparin, a compound used to fibrillize the tau in vitro.
What does research mean to you? Part of the reason that I came to UT Dallas was because of all the undergraduate research opportunities, foremost among them the Green Fellowship. My grandfather was diagnosed with Parkinson’s Disease when I was in high school, and ever since I have wanted to pursue a career that would enable me to conduct research in neurodegeneration. The Green Fellowship seemed like the perfect way to get involved in such research at a highly ranked and respected university.
Tell us about your journey. When I started working in Dr. Diamond’s lab I knew nothing about cell culture, running a flow cytometer, or the concepts behind neurodegenerative diseases beyond what I had read in my textbooks. In the beginning, I was completely overwhelmed and intimidated, but got over these inhibitions as I became more involved in my project. People were extremely patient and always willing to answer my questions and show me how to do things, and soon I felt quite comfortable with what I was doing. My project took a few interesting turns, and in the end turned out to be a complete dead end. Regardless, I look back on that semester as one of the highlights of my time at UTD, and I couldn’t be more grateful to all the people who made it possible. Participating in the Green Fellowship affirmed my passion for research and provided a preview of what graduate school would be like, and I highly recommend it for anyone interested in pursuing research.
Advice for Future Green Fellows
Be involved. Whatever you put into this experience is what you’ll get out of it, so don’t apply if you’re not passionate about research. Take the time to really find a lab that matches your research interests and what you’re wanting to study, and don’t be afraid to ask questions. Once in lab, make every effort to be involved and be present. As the semester goes on, the more you learn and understand about your project, the more exciting the research gets! Don’t get discouraged in the beginning, though - it takes a couple weeks (months) to get the hang of things.