Identifying Key Plasma Proteins in the Onset of Parkinson's Disease: Proteome-Wide Mendelian Randomization and Single-Cell RNA Sequencing Analysis

Abstract

Currently, the pathogenesis of Parkinson's disease (PD) remains enigmatic, primarily due to the scarcity of definitive diagnostic markers, thereby hampering both diagnosis and treatment. The urgent need for accessible plasma markers and targeted therapeutic agents has prompted us to employ various methodologies. We leveraged Mendelian randomization analysis, colocalization analysis, SMR analysis, and the HEIDI test to delve into the causal relationships between 2923 plasma proteins in the UK Biobank and PD. Our findings revealed that 21 plasma proteins, including CTF1 and STX4, may demonstrate causal relationships with PD. Further single-cell and bioinformatics analyses have shed light on the fact that 18 of these proteins exhibit differential expression across various brain cell types in patients with PD. These proteins are involved in crucial biological processes, including peptide binding, amide binding, amyloid-beta binding, endocytic vesicle formation, and the functioning of early endosomes. Notably, the PPI network exhibited interactions between ITGAM and HLA-DRA, as well as APOE, while APOE displayed interactions with APOA1, and SERPINE2 interacted with VNN2. Furthermore, our study demonstrates that plasma proteins, including CTF1, STX4, HPGDS, and APOA1, exhibit therapeutic potential for drug development based on gene-drug interaction predictions. While these findings provide a theoretical basis for the exploration of diagnostic markers and potential therapeutic targets for PD, extensive experimental validation is essential to confirm their potential in the future.

Keywords: Mendelian Randomization Analysis; Parkinson’s Disease; Plasma Proteins; Single-Cell RNA Sequencing Analysis; Summary Data-Based Mendelian Randomization Analysis.