Rosiglitazone alleviates Parkinson's disease phenotypes of Drosophila via dCTP-mediated inhibition of AGE-RAGE pathway.
Rosiglitazone alleviates Parkinson's disease phenotypes of Drosophila via dCTP-mediated inhibition of AGE-RAGE pathway.
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Original abstract
BACKGROUND: Parkinson's disease (PD) is an aging-related neurodegenerative disorder, which threatens the health and life of millions of patients worldwide, but remains incurable. Developing novel interventive strategy is urgent yet unmet. In recent years, it was well accepted that pathogenesis of PD closely correlated with aberrant glucolipid metabolism. The antidiabetic drug, Rosiglitazone (Rosi), one typical PPARγ agonist was found to exert neuroprotective effect. However, whether Rosi can rescue the PD-related phenotypes and the underlying mechanisms remain to be elucidated. METHODS: In present study, after Rosi administration, the PD phenotypes were characterized via immunofluorescent staining, climbing ability, lifespan assays, as well as transmission electron microscopy (TEM). Mechanisms were investigated by transcriptomics and MALDI-TOF-MSI analysis. The AGE-RAGE pathway was identified through KEGG screening and validated via qPCR and glyoxal cell experiments. Finally, the screened metabolite dCTP was replenished to PD drosophila to explore its therapeutic effects and mechanism. RESULTS: It showed that Rosi administration substantially ameliorated PD phenotypes, reduced LDs accumulation and restored mitochondrial quality control (MQC) in the PD drosophila brain. MALDI-TOF-MSI analysis demonstrated that Rosi administration elevated content of dCTP, which reduced in PD drosophila brain. Moreover, both Rosi and dCTP inhibited the over-activated AGE-RAGE/EGR1 pathway in PD context. CONCLUSIONS: In summary, present study for the first time revealed that Rosi and its downstream metabolite dCTP could serve as novel therapeutic option for PD by inhibiting AGE-RAGE/EGR1 pathway. It not only provided novel clues for treatment of PD but also highlighted the potential of drug repositioning.