Tolcapone

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

Halocyclopentadienes (HCPDs) are an emerging class of alicyclic disinfection by-products (DBPs) with high toxicity in disinfected drinking water. However, their potential precursors remain unclear, which hinders the understanding of their formation and further development of control strategies. In this study, two HCPDs, 1,2,3,4-tetrachloro-1,3-cyclopentadiene (TCC) and 1,2,3,4,5,5-hexachloro-1,3-cyclopentadiene (HCC), were identified in chlorinated lignin and tannic acid samples for the first time. The chlorination of four lignin-like and two tannic-like phenolic model compounds confirmed that guaiacol and digallic acid can produce HCPDs. According to their structures, ortho-substituents of phenolic compounds were speculated to be crucial for HCPDs formation. The simulated disinfection of catechol, 2-ethoxyphenol (2-EOP), 2-propoxyphenol (2-POP) and 3,4-dihydroxy-5-methoxybenzoic acid (DH-5-MBA) with different ortho-substituents demonstrated that three of these compounds can generate HCPDs, except catechol, which further indicates that ortho-substituents, such as the methoxy, ethoxy and propoxy groups, contribute to HCPDs generation. Guaiacol was the simplest compound for generating HCPDs, and possible formation pathways during chlorination were proposed. Seven hydroxy-chlorocyclopentadienes were tentatively identified and are likely important intermediates of HCPDs formation. Additionally, TCC and HCC were confirmed in tap water and chlorinated SRNOM samples with total concentrations up to 11.07 ng/L and 65.66 ng/L, respectively, further demonstrating the wide existence of HCPDs and their precursors. This study reports the clear precursors of HCPDs and provides a theoretical foundation for controlling HCPDs formation in disinfected drinking water.