PR002219 (Project)

Description:Occupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson's disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying this link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adult Drosophila model of Mn toxicity to recapitulate key Parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. We performed global metabolomics on flies at an early toxicity stage and identified metabolism of the B vitamin, biotin (vitamin B7), as a master pathway underpinning Mn toxicity with systemic, body–brain increases in Mn-treated groups compared to the controls. Using BtndRNAi mutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, Parkinsonism, and mitochondrial dysfunction, while in Mn-exposed wildtype flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)-differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated levels of biotin transporters compared to healthy controls, suggesting a potential role of biotin metabolism in PD. Taken together, our findings identified the compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and Parkinsonian pathology, providing a new basis for devising effective countermeasures against manganism and PD.