OBJECTIVE: To investigate the role of aberrant Dyrk1a expression in phosphorylation modification at the -synuclein serine 129 (Ser129) site to analyze its molecular mechanism in mediating apoptosis of PD. METHODS: The protein level of P--synuclein (Ser129), -synuclein, Bcl-2, Bax, active caspase 3, GSK3, PI3K, AKT, and cyclinD1 were detected. The mRNA transcript levels of Dyrk1a and DAT and protein levels of IL-1, IL-6, COX-2, and TNF- were detected. RESULTS: P--synuclein (Ser129), -synuclein, Bax, active caspase 3, GSK3, and cyclinD1 expressions were decreased in Dyrk1a-AAV-ShRNA ( < 0.05), and Bcl-2, AKT, and PI3K expressions were increased ( < 0.05). Increased TH protein expression was shown in Dyrk1a-AAV-ShRNA ( < 0.05). Dyrk1a mRNA was decreased in the Dyrk1a-AAV-ShRNA group ( < 0.05), and DAT mRNA was increased ( < 0.05). IL-1, IL-6, COX-2, and TNF- protein levels were decreased in Dyrk1al-AAV-Sh-RNA ( < 0.05). Transcriptome sequencing showed that Fam220a, which was expected to activate STAT family protein binding activity and participate in the negative regulation of transcription through RNA polymerase II and protein dephosphorylation showed differentially upregulated expression. The untargeted metabolome showed that the major compounds in the Dyrk1a-AAV-ShRNA group were hormones and transmission mediators and the most metabolism-related pathways. Fam220a showed differentially upregulated expression, and differentially expressed genes were enriched for the neuroactive ligand-receptor interaction, vascular smooth muscle contraction, and melanogenesis-related pathways. CONCLUSION: Abnormal Dyrk1a expression can affect -synuclein phosphorylation modifications, and dyrk1a knockdown activates the PI3K/AKT pathway and reduces dopaminergic neuron apoptosis. It provides a theoretical basis for the group to further investigate the molecular mechanism.