Structural and Kinetic Basis of Prion Replication

Prion proteins change shape from a normal folded form into a rogue, infectious one—and this project uses nanoscopic imaging to watch that transformation happen in real time. The central problem is that no one knows exactly what structural change turns a harmless prion protein into a self-replicating killer, or how that rogue shape then forces other proteins to adopt the same deadly fold. Without this knowledge, prion diseases like Creutzfeldt-Jakob disease remain untreatable and invariably fatal. The researchers have developed a technique called transient amyloid binding (TAB), which lets them observe individual prion particles over hours as they grow and change shape. If successful, this work could reveal the molecular rules that govern prion replication—rules that may also apply to other diseases where proteins misfold and clump, such as Alzheimer’s and Parkinson’s. The project is fundamentally curiosity-driven, aimed at understanding a basic biological mechanism. But similar fundamental work on protein folding has already led to drugs for cystic fibrosis and new diagnostic tools for neurodegenerative disease. A clear picture of how prions replicate could eventually point toward molecules that block the process, or help identify which protein aggregates in the body are dangerous and which are harmless.