Glutamate-cysteine ligase as a diagnostic biomarker and therapeutic target in Parkinson's disease: a multi-omics and experimental study

Parkinson's disease (PD) is a major global health challenge, and the identification of highly specific and easily detectable blood markers is critical for early diagnosis and intervention in PD. In this study, we recruited 21 patients with Parkinson's disease and 16 healthy controls. We examined blood samples for marker screening using targeted metabolomics and proteomics and machine learning techniques. We found that glutathione metabolism was enriched in Parkinson's disease patients, and the glutathione synthesis rate-limiting enzyme Glutamate-cysteine Ligase catalytic subunit (GCLC) was significantly down-regulated in Parkinson's disease patients. In vitro, we utilized rat astrocytes and constructed interference and overexpression vectors based on sequencing results. We explored their effects on cell proliferation, apoptosis and mitochondrial function by CCK-8, flow cytometry, and RT-PCR assays. In vivo, we established a mouse model of MPTP-induced Parkinson's disease. After intervening with the target gene using lentivirus, we assessed the motor function of the mice by climbing pole tests, rotarod tests, and open field tests. The results showed that GCLC was involved in the pathogenesis of Parkinson's disease and was associated with dopaminergic neuron deficits and motor deficits. These results suggest that GCLC may serve as a promising biomarker for early diagnosis and a potential therapeutic target in PD.