"From Atoms to Systems: A Multi-Scale Approach to Modeling and Correcting Neurodegenerative Disease Pathology"

Abstract
Protein misfolding and aggregation has been linked to neurodegenerative disease, but the specific toxic species and mechanisms of disease progression initiated by these species remain unknown and uncharacterized. By combining low-resolution data from structural biology experiments with atomistic molecular dynamics simulations, we built structural models of aggregation intermediates, and used these models to guide protein engineering efforts to determine neurotoxicity of particular protein oligomeric species. To further explore the mechanisms of neurotoxicity instigated by misfolded protein oligomers, we developed a multi-scale approach to characterize dysregulated inter- and intra-cellular signaling pathways in human tissue and a cellular culture system. We then leveraged our knowledge of differences between the disease and healthy systems to correct the aberrant molecular signaling reaction of cells to misfolded protein species and rescue neuron viability. The integration of methodologies from structural and systems biology holds potential to engineer diagnostic and therapeutic solutions based on knowledge of molecular species and their role in pathological disease processes.

Elizabeth Proctor is a post-doctoral researcher in the Department of Biological Engineering at MIT, where she integrates experimental and computational systems biology methods to uncover cellular communication and signaling networks implicated in disease.