Work

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

Year: 2025

Type: article

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 π-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 α-synuclein (αS) fibrils, a hallmark of Parkinson's disease (PD), including amplified fibrils from patient samples; (2) monitoring early misfolding and oligomer formation during αS aggregation; and (3) selective imaging of αS condensates formed by liquid-liquid phase separation (LLPS). In all three cases, we show that our probes have high levels of selectivity for αS versus other aggregating proteins. These properties enable one to study the interplay of αS and tau in amyloid aggregation and the mechanisms underlying neurodegenerative disorders.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.4c17933

Authors: Yarra Venkatesh, Karthik B. Narayan, Tobias Baumgart, E. James Petersson

Institution: University of Pennsylvania

Language: English

Topic: Molecular Sensors and Ion Detection

Subfield: Spectroscopy

Field: Chemistry

Domain: Physical Sciences

Open Access status: green