New transcriptome-based gene expression networks on levodopa-induced dyskinesia in Parkinson's disease

Levodopa-induced dyskinesia (LID) is a motor complication of chronic use of levodopa in Parkinson's disease (PD), characterized by involuntary movements that negatively impact the overall well-being of people with PD. The molecular mechanisms of LID are still poorly understood, and the present study aims to identify differentially co-expressed genes associated with LID. We analyzed peripheral blood samples from 46 participants, consisting of 15 people with PD and LID (PD-D), 11 people with PD without LID (PD-ND), and 20 sex- and age-matched individuals in the control group. RNA total sequencing was performed on these samples. After quality control, we conducted differential expression analysis using DESeq2, and our results revealed a set of 30 differentially expressed genes, with 14 genes showing alterations in PD-D and 16 in PD-ND. We also conducted co-expression analyses using CEMitool package to identify exclusive gene modules in LID, where we identified 12 co-expressed genes exclusives this condition. Additionally, we identified differential gene co-expression networks where six unique PD-D hub genes were observed, involved in 23 gene-gene interactions. In all analyses, we identified novel genes associated with PD and LID, along with a convergence of enriched biological processes and metabolic pathways for the identified genes. Among these, mitochondrial dysfunction, dysregulation of lipid metabolism, endoplasmic reticulum stress, alterations in protein synthesis, and neuroinflammation. In summary, we observed significant changes in the gene expression and gene co-expression networks in LID, within a admixed population. These results support the previous findings of maladaptative plastic changes in the basal ganglia leading to the development of LID, including a chronic pro-inflammatory state in the brain.