Description:

Structural Targeting of Tau Propagation: A New Therapeutic Platform for Neurodegeneration 
Despite their prevalence and devastating impact on human health, there are currently limited effective treatments for most neurodegenerative diseases. A key feature of many of these disorders is the accumulation of misfolded protein aggregates that adopt disease-specific conformations and spread in a prion-like manner. Working in collaboration with computational biologists and biophysicists, we designed and characterized a minimal peptide sequence that recapitulates the structural folds observed in a class of tauopathies marked by selective seeding of the 4R, but not 3R, isoform of tau, as seen in diseases such as progressive supranuclear palsy and corticobasal degeneration. Using this "miniPrion" as a structural and functional model, we developed tau-binding protein-like polymers (PLPs) that inhibit fibril propagation. We demonstrate the effectiveness of these PLPs in halting tau spread across multiple models, including in vitro systems, cell cultures, human-induced pluripotent stem cell-derived cortical organoids, and mouse models. This work represents a conceptual advance that offers a new therapeutic strategy for combating protein aggregation-driven neurodegenerative diseases.

Bio
Andrew Longhini is an Assistant Project Scientist at the University of California, Santa Barbara. His research focuses on the molecular and structural mechanisms of neurodegenerative diseases, with an emphasis on protein aggregation and therapeutic design. He received his Ph.D. in Biochemistry from the University of Maryland, College Park, where he studied the structural biology of RNA elements using Nuclear Magnetic Resonance. His recent work has been supported by the California Institute of Regenerative Medicine and leverages multiple collaborations with faculty at Northwestern. This work involves the development of novel protein-like polymers to inhibit tau fibril propagation, offering new therapeutic strategies for tauopathies.