Work

Intracellular Catalytic Photooxygenation of α‐Synuclein Amyloid

Year: 2025

Type: article

Abstract: The amyloid aggregation of α ‐synuclein is a central pathological hallmark of various synucleinopathies, including Parkinson disease. Consequently, developing strategies to eliminate α ‐synuclein amyloids represents a promising therapeutic approach. While amyloid‐selective photooxygenation catalysts have shown potential in mitigating α ‐synuclein‐related molecular pathologies, such as aggregation, seed activity, and amyloid‐associated cytotoxicity, no effective methods have been established for targeting intracellular α ‐synuclein amyloids. Here, inspired by the structural features of an α ‐synuclein‐selective positron emission tomography probe, we designed and synthesized catalyst 11 , a novel compound optimized for intracellular applications. By balancing lipophilicity for membrane permeability, water solubility, and long‐wavelength light absorption, catalyst 11 promotes the first photooxygenation of α ‐synuclein amyloids within living cells. Notably, catalyst 11 exhibits amyloid selectivity via a photodecay modulation mechanism upon amyloid binding. Our findings reveal significant photooxygenation of all four methionine residues in α ‐synuclein and crosslink formation suggestive of histidine oxygenation in cells. These results showcase catalyst 11 as a promising lead compound for advancing both chemical and biological investigations aimed at therapeutically targeting α ‐synuclein amyloidosis.

Source: ChemistryEurope

DOI: 10.1002/ceur.202500192