Polyhalogenated Carbazole Impairs Dopaminergic Neurons through Dysregulation of Liquid–Liquid Phase Separation in <i>Caenorhabditis elegans</i>

Polyhalogenated carbazoles (PHCZ) are emerging organic pollutants derived from a variety of natural and synthetic sources. While PHCZ have raised environmental concerns due to its persistence, bioaccumulation, and widespread distribution, its neuronal toxicity remains largely understudied. Here, the general and neuronal toxicity of PHCZ using the model organism Caenorhabditis elegans (C. elegans) is evaluated. It is found that PHCZ can induce significant dopaminergic neurodegeneration, in addition to exhibiting general toxicity affecting development and male gamete differentiation. Mechanistically, PHCZ promote liquid-liquid phase separation (LLPS) of the Parkinson's disease (PD)-associated protein α-synuclein (α-syn), and reduces the fluidity of the resultant condensate both in vitro and in vivo. PHCZ disrupts general protein homeostasis and specifically activates the unfolded protein response in the ER (UPR^ER) through the IRE-1 signaling axis. Moreover, PHCZ impairs mitochondrial functions, providing another mechanistic link to neuronal degeneration. Thus, this study uncovers a hitherto unrecognized neuronal toxicity of PHCZ, which is partly attributed to their capacity to dysregulate LLPS and UPR^ER, offering new insights into their potential health risks.