Songi Han and Nancy Ratner Professor of Chemistry at Northwestern University’s Weinberg College of Arts and Sciences. To date, through her groundbreaking research, she has achieved tremendous progress in decoding protein misfolding. Han and her team aimed to investigate how initially disordered tau proteins converge into highly ordered fibril structures, which have implications for neurodegenerative diseases.
This pioneering research then allowed the team to create a synthetic, prion-like tau protein. Han’s group found that water was a surprising driving force keeping misfolded proteins together. “Water is a fluid molecule, but it still has structure,” Han explained, emphasizing the importance of this element in the formation of tau fibrils.
This new research, published in the Proceedings of the National Academy of Sciences, focuses on a small region of tau called jR2R3. This stretch consists of 19 contiguous amino acids. Michael Vigers, a former Ph.D. student in Han’s laboratory, acted as the first author of the study. The team utilized Cryo-EM to map the structural details of the fibrils from various angles, creating a clearer picture of how these proteins behave.
Han observed that once a tau fibril has formed, it’s essentially stable for all time. “Once a tau fibril is formed, it doesn’t go away,” she stated. This tenacity enables the tau fibrils to spread by still exerting their influence over other innocent bystander tau proteins, corrupting them and folding them into the same shape. It’ll catch mismodified naïve tau and fold it back into that same structure. And it’s going to be able to continue doing this ad infinitum,” she continued.
The implications of Han’s research go far past ivory tower interests. These results may help inform new diagnostic approaches for neurodegenerative diseases associated with tau proteins, including frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease. These are diseases such as chronic traumatic encephalopathy and progressive supranuclear palsy. “Creating self-propagating tau fragments that can recreate the fibril structure and misfolding that is unique to each tauopathy disease is a crucial step forward in our ability to understand and model these complex diseases,” Han explained.
Moreover, the study highlights a significant bottleneck in diagnosing neurodegenerative diseases: the reliable generation of tau fibrils to serve as targets for diagnostics. “Physicians determine the diagnosis by administering a patient survey and by examining a collection of symptoms, like sleep patterns and memory,” Han noted, pointing out that current diagnostic methods often lack definitive biomarkers.