Project R-17035

LiCo: Development of a structural biology platform for Alzheimer's research (Research)

Biological function is governed by the dynamic molecular conformations and interactions. Understanding these dynamics is essential for cellular processes in health and disease, yet traditional structural biology methods often provide only static snapshots or ensemble average that mask rare, transient intermediates. Single-molecule Förster Resonance Energy Transfer (smFRET) can bridge this gap, but its use is limited by low throughput and lack of spatial context, preventing large-scale screening or probing dense molecular environments. This project aims the development of LiCo, a line-based confocal microscope that parallelizes smFRET acquisition to increase molecular throughput by orders of magnitude without sacrificing molecular-level sub-nanometer resolution. By overcoming sampling constraints, LiCo enables the structural characterization of proteins within complex, heterogeneous environments. We will apply LiCo to the protein Tau, a key driver of Alzheimer’s disease, to map a comprehensive conformational atlas to identify rare structural tipping points that trigger neurotoxic aggregation. This will establish a framework for structure-guided drug discovery to stabilize Tau and halt disease progression. Beyond Tau, LiCo offers a universal platform within structural biology, as it is designed as a one-stop-shop add-on module, transforming conventional fluorescence microscope into a fast single-molecule stations.

01 November 2026 - 31 October 2030