Research Department: Center for Alzheimer's and Neurological Diseases
Graduation Date: Spring 2020
Abstract:Microtubule-associated protein tau (Tau) is an intrinsically disordered protein found mainly in the neurons of the central nervous system, where it stabilizes the microtubules of the neuronal cytoskeleton. However, in diseases known as tauopathies, Tau aggregates into filaments and neurofibrillary tangles (NFTs), which are found in Alzheimer’s disease and Pick’s disease, as well as corticobasal degeneration, chronic traumatic encephalopathy, various dementias, and Parkinson’s disease (among others). Tau aggregation is modeled as a prion-like system, wherein a monomer in its native state misfolds or is misfolded into a state that can induce the misfolding and aggregation of other Tau proteins. While the structure of the seed competent state, the misfolding process, or the aggregate seeding mechanism is not well understood, we propose that Tau, which is hyperphosphorylated in tauopathies, adopts a seed-competent conformation stabilized by intramolecular charge-charge interactions, and that phosphorylation plays a role in shifting these charge-charge interactions from a native state that suppresses Tau’s aggregation propensity into a prion-like state that promotes the aggregation of Tau. We found that Tau has a distinct phosphorylation phenotype in patients with and without Alzheimer’s disease, and that this phosphorylation pattern leads to a significant alteration of Tau’s “native” charge patterning. In addition, tau in an aggregation-prone state seems to have a unique set of conformers and topologies not shared by non-aggregate seeding tau samples that corresponds to charge-charge interactions formed or suppressed by the hyperphosphorylation and altered charge distribution of the diseased tau of Alzheimer’s patients.
What does research mean to you? Research is a process of discovery. Every day, you get a chance to learn something new, something that nobody else has found yet, not in any textbook, and potentially could lead to new insight, or a useful development- even if that discovery is that your experiment or procedure didn’t work. Hopefully all the hints and failures and discoveries add up to interesting knowledge and useful application that can improve science, medicine, and human lives all over the world.
Tell us about your journey. I began doing research as a freshman in Dr. Eric Kildebeck’s lab at UT Dallas, studying the use of chimeric, engineered proteins to interact with the immune system and suppress or modulate antibody and t-cell mediated immune response, as well as the interaction of the NF- κB family of transcription factors with the Leukemia inhibitory factor gene. I then began the Green Fellowship, where I have been studying Microtubule-Associated protein Tau in the lab of Dr. Lukasz Joachimiak, where I will be continuing as a SURF Affiliate after the conclusion of the Green Fellowship. In the future, I am hope to join a MD/PhD program and doing research on human disease and treatment.
Advice for Future GreenFellows
Make sure you’re doing this for the right reasons-if you’re not passionate or at least strongly curious about the idea of doing research for your career, this program might not be for you. The Green Fellowship is a job- an interesting, informative, and challenging one. Make sure you have the interest and motivation to enjoy, or at least gain something from five months of doing research full-time. It is not for everyone. Sort out your college schedule and degree planning, so you can comfortably apply to the program without sacrificing or cramming classes in near the end. Keep in mind what interests you as a researcher but be open to working in new areas and paradigms. Ask a lot of questions, strive to understand both the science and the methodology, and own your contribution to your project and your lab’s research. Work hard, keep good notes, and do your homework-proper preparation preempts painful prospects. Stay engaged with your lab, the other fellows, and your friends and interests.
If you have any questions about anything at all, or would like advice about applying to the Green Fellowship, or even whether it might be for you, feel free to reach out to me at [email protected].