Multi-omics analysis reveals the protective role of transcriptional enhancer factor and the pathogenic mechanism of monocytes in Parkinson's disease.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14+CD16+ monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.