Longitudinal Data-based Pathogenesis Interpretation And Drug Discovery For Onset And Progression Of Parkinson's Disease

Parkinson's disease(PD)is a complex neurodegenerative disease.Although the pathological features are obvious,the pathogenesis is still unclear.There is no cure for PD at present.The rapid development of omics technologies provides opportunities and challenges to understand the molecular mechanism of PD and to find more rational treatments.We initially investigated how PD occurs and develops based on longitudinal clinical,longitudinal blood RNA-seq,and baseline blood DNA methylation data.We firstly performed a transcriptome-wide association study to confirm the coherence between clinical severity and blood RNA-seq data.By analyzing the conversion from prodromal subjects to PD patients,we found that dysfunction of olfactory conduction at the molecular level is a precursor for PD,and subsequently discovered an olfactory receptor OR8D1 as a candidate warning marker.Furthermore,we theoretically inferred and initially validated by cellular experiments that withaferin A could promote the differentiation of neural stem cells into dopaminergic neurons with great potential to treat early stage PD patients.Next,we identified 325 genes significantly related to PD progression based on the longitudinal transcriptome-association analysis.Most of these genes were downregulated during PD progression and involved in dopaminergic synapses and ferroptosis,on which basis,we further recommended some drugs that suitable for severe PD patients.Taking the x Cell method,we speculated that the proportion of nerve cells in blood also decreased as PD progresses.At last,using methylome-wide association study,we found DNA methylation didn't change immediately as symptoms occurred,but showed a delay;and methylation may affect PD progression through long-term regulation of gene expressions.Our results provided new insights into the pathogenesis of PD,and have certain application values in clinical diagnosis and treatments.