Work

Delving into the possible role of Ochratoxin A in Parkinson's disease: a computational study spotlighting the potential mechanisms of action

Year: 2025

Type: article

Abstract: Ochratoxin A (OTA) is a widespread food contaminant relevant to food safety that has various toxic effects including nephrotoxicity and neurotoxicity. Evidence suggests OTA may contribute to Parkinson's disease (PD) pathogenesis acting at multiple levels along the adverse outcome pathway (AOP), though molecular targets and underpinning mechanisms remain unclear. Using a computational pipeline based on molecular modelling techniques, which are well-established methods to elucidate protein-ligand interactions, this study investigated key events in the PD AOP where the current state-of-the-art suggests OTA and its congeners may play a role, i.e. inhibition of cathepsins B, D, and L (relevant for α-synuclein proteostasis), and Complex I (responsible for mitochondrial dysfunction). The study revealed that neither OTA nor its congeners could interact with cathepsin B, but some of them displayed differential binding with cathepsins D and L. The debated metabolites ochratoxin hydroquinone and quinone could favourably interact with the catalytic residue of the former and the latter, respectively. Additionally, OTA and ochratoxin quinone showed binding to Complex I in a rotenone-like fashion, suggesting its possible inhibition. These outcomes well-aligned with the current comprehension of OTA-PD relationship by providing deep mechanistic insights correlating OTA exposure and PD pathogenesis and revealing a novel and multi-tiered mechanism where OTA and metabolites may affect α-synuclein proteostasis and mitochondrial function. This could not only explain previous experimental observations, but also lays a knowledge-based groundwork for targeted investigations into OTA's role in PD pathogenesis. • OTA and congeners have been linked to PD by multiple AOP molecular targets. • OTA and OTQ may inhibit Complex I possibly disrupting mitochondrial function. • OTA and congeners show binding to cathepsins D and L, but not B. • The binding to cathepsins by OTA and congeners may impair α-synuclein proteostasis. • NAMs as in silico approaches provide toxicology insights detailed at molecular level.

Source: Food Research International

DOI: 10.1016/j.foodres.2025.117532