Seminars

Proteins are vital biomolecules that do most of the critical functions in the body, including structural roles, enzymatic activity, and regulation of metabolism. Tau proteins are present at micromolar levels in the brain, and function there to regulate the dynamics, stability and properties of cytoskeletal microtubules. Under pathological conditions, tau forms paired helical filaments (PHFs) that aggregate to form intracellular neurofibrillary tangles (NFT), which are one of the hallmarks of Alzheimer’s Disease (AD). In addition to AD, these tau NFTs occur in at least 26 other phenotypically distinct neurodegenerative diseases, termed tauopathies. For all neurodegeneration, tau transmission from across the brain occurs in a prion-like manner, exacerbating degeneration and worsening symptoms. However, the detail on the molecular and cellular contributions are still an area of active research, limiting current therapeutic success.

In this talk I will describe our studies on the individual steps in tau transmission relevant to disease; namely, tau intracellular aggregation, release, cellular uptake and seeding activity, with a focus on determining the differences in wild-type (physiological) tau vs phosphorylated, aggregation-prone tau. We have employed several biophysical techniques to study the aggregation propensity of different tau isoforms, with a focus in particular on how phosphorylation effects aggregate formation. From a cellular perspective, we have also been studying tau uptake and find that there are several routes for tau protein to enter the cell. Further, we demonstrated that cells take up more monomeric tau protein when pre-phosphorylated. Using an extracellular vesicle (EVs)-assisted tau neuronal delivery system, we show that phosphorylated tau present in EVs, when added to differentiated SH-SY5Y cells, induced more efficient tau transfer, showing much higher total tau levels and increased tau aggregate formation as compared to wild type tau. In addition to the differences in uptake behavior, protein properties also alter cellular pathway activation differently, such as pro-inflammatory responses. On-going studies are focused on in vivo studies and identifying potential sites for therapeutic intervention.

Anne Skaja Robinson became Head of Carnegie Mellon University’s Department of Chemical Engineering in 2018 and Trustee Professor of Chemical Engineering in 2019. Prior to her current appointment, she served as Chair of Chemical and Biomolecular Engineering and Boh Professor of Engineering at Tulane University. She started her academic career at the University of Delaware, where she ultimately became a Full Professor and Associate Chair in Chemical Engineering. Having received both her B.S. and M.S. in Chemical Engineering from Johns Hopkins University, and her Ph.D. in Chemical Engineering from the University of Illinois at Urbana-Champaign, Robinson has earned many honors, including a DuPont Young Professor Award, and a National Science Foundation Presidential Early Career Award for Science and Engineering, and most recently the 2022 Marvin Johnson Award from the ACS BIOT division. She is also a fellow of both the American Institute for Medical and Biological Engineering, and the American Institute of Chemical Engineers. Dr. Robinson’s research focuses on three primary areas of bioengineering: expression and characterization of integral membrane proteins, especially G-protein coupled receptors; understanding and controlling protein aggregation; and cellular mechanisms controlling protein quality and human disease.