Unveiling Lipid Droplet Dynamics in Parkinson’s Disease via a Polarity-Responsive Alkenyl Indole-Based Fluorophore

Lipid droplets (LDs) are dynamic organelles implicated in Parkinson’s disease (PD) pathology, yet their polarity dynamics and therapeutic relevance remain poorly understood. Herein, we rationally designed a polarity-responsive alkenyl indole-based fluorophore, PD3, through systematic molecular engineering to enable real-time tracking of LD polarity in PD models. By modulating intramolecular charge transfer (ICT) effects via electron-donating/withdrawing substitutions, PD3 exhibited exceptional polarity sensitivity, with a dramatic fluorescence enhancement in low-polarity environments and negligible viscosity interference. Density functional theory calculations confirmed that the polarity response originated from ICT-driven solvatochromism and solvent-dependent internal conversion rates. In rotenone-induced PD cellular models, PD3 revealed significant LD accumulation (4.2-fold intensity increase, 74% higher LD density, and 46% enlarged diameter) and organelle crosstalk, particularly with the endoplasmic reticulum (ER) and mitochondria. Furthermore, PD3 -enabled evaluation of PD drugs demonstrated that amantadine (AMA) and pramipexole (PPX) restored LD homeostasis, linking their therapeutic effects to LD modulation. Ex vivo studies in methyl-phenyl-tetrahydropyridine (MPTP)-induced PD mice confirmed LD accumulation in brain tissues, correlating with motor deficits and neuronal loss in the substantia nigra. This work establishes PD3 as a powerful tool for deciphering LD-associated PD pathology and advancing LD-targeted therapeutic strategies.