A new technology to probe molecular interaction in cells at high throughput

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Protein oligomers and aggregates are pillars of many cellular processes and can be associated with a number of life-threatening neurodegenerative diseases. These processes are often context-dependent but are hard to detect in situ with available technologies. The ideal instrument can target specific proteins of medical interest in their physiological contexts, resolve nano-distances (1-100 nm) and capture dynamics of association and dissociation (ns-ms). The DiffusOMICS project aims to fill this methodological gap by prototyping a high-throughput fluorescence-based approach able to measure the rotational diffusion properties of molecules in vivo and in situ. The concept is based on our recent publication, where we utilize intelligent fluorescent probes together with polarized light to investigate the rotational dynamics of large molecular complexes. Rotational diffusion is highly sensitive to change in mass making the technique ideal to detect the presence of aggregates and report on molecular size and local viscosity. Due to the nature of the signal, the measurements can be done in cells and tissues at high throughput, making the technology appealing for industrial screening applications. The goal of the project is to establish both the technological foundation and the collaborations needed to develop a prototype instrument and to record the very first high-throughput molecular interaction maps in neurons. DiffusOMICS possesses all the essential qualities to become a game-changing technology for drug screening due to its sensitivity, specificity and speed, making it suitable for automated recordings. DiffusOMICS maps will carry information on the whole population of aggregates localized in different neuronal compartments and can track changes in aggregation responses to drug perturbations and mutagenesis in neuronal proteins. The outcome will be key to engage industrial strategic partners and it paves the way for a new paradigm of drug screening in situ.