Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by the selective death of dopaminergic neurons in the substantia-nigra of the midbrain. The primary symptoms include tremors, rigidity, bradykinesia, and balance deficits (Ben-Shlomo et al., 2024). Although the exact cause of PD remains unknown, current treatments, such as medication and surgery, only alleviate symptoms without stopping disease progression (Vijiaratnam et al., 2021). Therefore, understanding the specific mechanisms underlying dopaminergic neuron death is essential for developing effective treatments for PD.

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a crucial role in the pathogenesis of Parkinson's disease (PD)(Dixon et al., 2012). The characteristics of ferroptosis closely mirror the pathological changes observed in PD, with the associated genes showing strong links to the disease. In PD patients, iron and α-synuclein coexist within the Lewy bodies of the midbrain. As a metal-binding protein, α-synuclein undergoes conformational changes upon binding to iron, resulting in pathological overpression that promotes disease progression (Dong-Chen et al., 2023).

GOT1, a critical transaminase, has been identified as a key metabolic gene in models of Alzheimer's, Parkinson's, and Huntington's diseases through analyses of the Gene Expression Omnibus, Recon 3D human metabolic model, and DrugBank databases (Li et al., 2020). This underscores a strong association between GOT1 and the pathogenesis of Parkinson's disease. In these models, GOT1 and six other metabolic genes were found to be downregulated, highlighting its potential role in PD. Additionally, GOT1 has been recognized as pivotal in studies of ferroptosis. In pancreatic ductal adenocarcinoma (PDAC) cells, the KRAS-specific downregulation of glutamate dehydrogenase (GLUD1) and upregulation of GOT1 facilitate the conversion of glutamine to aspartate. This process, mediated by GOT1, supports NADPH production, thereby maintaining redox balance (Chae and Kim, 2018). Research by Kremer DM et al. demonstrated that inhibiting GOT1 in pancreatic cancer cells induces ferroptosis by disrupting mitochondrial metabolism and releasing unstable iron (Kremer et al., 2021).

A review of existing literature, along with the Reactome pathway database, identifies GOT1 as a key enzyme in the methionine salvage pathway, essential for converting 4-methylthio-2-oxobutyrate (MTOB) to methionine (Catanesi et al., 2021). Methionine, a crucial sulfur-containing amino acid, plays a significant role in the biosynthesis of glutathione, a vital antioxidant. A metabolome-wide association study (MWAS) of Parkinson's disease, utilizing liquid chromatography and high-resolution mass spectrometry (LC-HRMS), analyzed untargeted metabolomics data from serum and cerebrospinal fluid in two population-based case-control groups. This study suggests a strong correlation between methionine metabolism and Parkinson's disease (Paul et al., 2023). Methionine is critical for ferroptosis, as it is a key component in glutathione biosynthesis; however, abnormal methionine metabolism can lead to excessive lipid peroxide accumulation, exacerbating ferroptosis (Uceda et al., 2023). The specific role of GOT1-mediated methionine metabolism in causing ferroptosis in midbrain dopamine neurons remains unclear. This project aims to elucidate this mechanism in Parkinson's disease progression, offering new insights and potential therapeutic targets for clinical treatment.