Abstract
BACKGROUND: The mTOR pathway is crucial in controlling the growth, differentiation, and survival of neurons, and its pharmacological targeting has promising potential as a treatment for Parkinson's disease. However, the function of mTORC1 downstream proteins, such as RPS6K, EIF4EBP, EIF-4E, EIF-4G, and EIF4A, in PD development remains unclear. METHODS: We performed a Mendelian randomization study to evaluate the causal relationship between mTORC1 downstream proteins and Parkinson's disease. We utilized various MR methods, including inverse-variance-weighted, weighted median, MR-Egger, MR-PRESSO, and MR-RAPS, and conducted sensitivity analyses to identify potential pleiotropy and heterogeneity. RESULTS: The genetic proxy EIF4EBP was found to be inversely related to PD risk (OR = 0.79, 95% CI = 0.67-0.92, p = 0.003), with the results from WM, MR-PRESSO, and MR-RAPS being consistent. The plasma protein levels of EIF4G were also observed to show a suggestive protective effect on PD (OR = 0.85, 95% CI = 0.75-0.97, p = 0.014). No clear causal effect was found for the genetically predicted RP-S6K, EIF-4E, and EIF-4A on PD risk. Sensitivity analyses showed no significant imbalanced pleiotropy or heterogeneity, indicating that the MR estimates were robust and independent. CONCLUSION: Our unbiased MR study highlights the protective role of serum EIF4EBP levels in PD, suggesting that the pharmacological activation of EIF4EBP activity could be a promising treatment option for PD.