Assembly and Peptide Cross Talk in Amyloid Systems

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Michael T. Bowers from the University of California at Santa Barbara to study how proteins and peptides assemble and “talk” to each other. The assembly of peptides or proteins into clumps or aggregates are associated with a number of human diseases, including the neurodegenerative disease amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and type-2 diabetes (T2D). This project will very accurately determine the specific sizes of these aggregates by a method called ion mobility based mass spectrometry and visualize their shapes using a method call atomic force microscopy. When combined with computational simulations, these studies will provide detailed information on how these peptides assemble into aggregates and what these aggregates look like at the molecular level. In addition, the studies will show how the peptide aggregates from these different diseases interact or “talk” with each other. This study will provide graduate and undergraduate students, including those from underrepresented minority groups with training in experimental and computational chemistry, as well as instrument development. Furthermore, the project will allow graduate students to engage high school students on their pathway to STEM careers. Understanding peptide assembly in solution and in vivo is difficult because traditional methods of study only yield ensemble averaged results, not results on the structure and distribution of oligomers as a function of oligomer number. Here methods are described that allow these measurements to be made, including ion mobility spectrometry and atomic force microscopy. Prior results have demonstrated these methods are robust and when coupled with high level molecular dynamics simulations yield oligomer structures as a functions of size, and how oligomer distributions change with solution parameters. In this proposal these methods are directed to key fragments of proteins responsible for ALS, specifically superoxide dismutase-1 and transactive response DNA binding protein 43. Oligomer structures and distributions are obtained along with variations in response to key disease-oriented mutations. These key ALS peptide systems are then mixed with fragments of A-beta-42, the peptide primarily responsible for AD, as well as hormone islet amyloid polypeptide, the peptide responsible for islet amyloid T2D. The assembly of both systems in the mixtures will be monitored to observe whether potential catalytic acceleration of the assembly process occurs. The goal is to understand the epidemiological observation that these diseases interact and to do so at the molecular level. Taking the potential for cross-talk between the disease related aggregates into account could provide a strategy for the development of new therapeutics to treat these aggregate dependent diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.