Title : The loss of PINK1 function alters molecular pathways in human fibroblasts
Abstract:
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Mutations in the PINK1 and PRKN genes have been linked to early-onset PD and are among one of the most frequent causes for inherited, recessive PD. PINK1 and PRKN together eliminate damaged mitochondria through a mitophagy pathway and the failure of this stress-dependent protective pathway might be linked to pathogenesis of PD. In fact, several studies have shown increased mitochondrial damage and the involvement of mitochondrial quality control in PD. Therefore, it is likely that failure of the PINK1/PRKN pathway also plays a role for idiopathic disease. However, a specific signature of mitophagy failure is not known yet. Here, we used transcriptomic and metabolomics analysis of human fibroblast samples with PINK1 complete loss of function, partial loss of function, and wild type to find such molecular fingerprint. We identified genes differentially expressed by PINK1 loss of function and found that they were enriched in pathways including complement system, STAT3 signaling, axonal guidance signaling and serotonin degradation. Additionally, using weighted gene co-expression network analysis, we found that PINK1 loss of function was associated with upregulated immune response and completement activation. Integrative analysis between transcriptomics and metabolomics revealed enriched purine metabolism. We validated the top genes and pathways other independent RNAseq experiments and in the wet lab. Our study nominates several molecular pathways that can be used as potential surrogates for loss of PINK1 function. These pathways can now be further exploited as biomarkers for mitophagy function and might be important for patient stratification in the future.
