Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein

Yarra, V.; Narayan, K. B.; Baumgart, T.; Petersson, E. J.

doi:10.1101/2025.01.07.631748

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bioRxiv · 10.1101/2025.01.07.631748

Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein

Yarra, V.·Narayan, K. B.·Baumgart, T.·Petersson, E. J.

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Abstract

Molecular rotor-based fluorophores (RBFs) that are target-selective and sensitive to both polarity and viscosity are valuable for diverse biological applications. Here, we have designed next-generation RBFs based on the underexplored bimane fluorophore through either changing in aryl substitution or varying {pi}-linkages between the rotatable electron donors and acceptors to produce red-shifted fluorescence emissions with large Stokes shifts. RBFs exhibit a twisted intramolecular charge transfer mechanism that enables control of polarity and viscosity sensitivity, as well as target selectivity. These features enable their application in: (1) turn-on fluorescent detection of -synuclein (S) fibrils, a hallmark of Parkinsons disease (PD), including amplified fibrils from patient samples; (2) monitoring early misfolding and oligomer formation during S aggregation; and (3) selective imaging of S condensates formed by liquid-liquid phase separation (LLPS). In all three cases, we show that our probes have high levels of selectivity for S versus other aggregating proteins. These properties enable one to study the interplay of S and tau in amyloid aggregation and the mechanisms underlying neurodegenerative disorders.

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Yarra, V., Narayan, K. B., Baumgart, T., Petersson, E. J.. 2025-01-09. Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein. https://doi.org/10.1101/2025.01.07.631748

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