Dysregulation of Human Somatic piRNA Expression in Parkinson's Disease Subtypes and Stages

Piwi interacting RNAs (piRNAs) are small non-coding single-stranded RNA species 20-31 nucleotides in size generated from distinct loci. In germline tissues, piRNAs are amplified via a "ping-pong cycle" to produce secondary piRNAs, which act in transposon silencing. In contrast, the role of somatic-derived piRNAs remains obscure. Here, we investigated the identity and distribution of piRNAs in human somatic tissues to determine their function and potential role in Parkinson's disease (PD). Human datasets were curated from the Gene Expression Omnibus (GEO) database and a workflow was developed to identify piRNAs, which revealed 902 somatic piRNAs of which 527 were expressed in the brain. These were mainly derived from chromosomes 1, 11, and 19 compared to the germline tissues, which were from 15 and 19. Approximately 20% of somatic piRNAs mapped to transposon 3' untranslated regions (UTRs), but a large proportion were sensed to the transcript in contrast to germline piRNAs. Gene set enrichment analysis suggested that somatic piRNAs function in neurodegenerative disease. piRNAs undergo dysregulation in different PD subtypes (PD and Parkinson's disease dementia (PDD)) and stages (premotor and motor). piR-has-92056, piR-hsa-150797, piR-hsa-347751, piR-hsa-1909905, piR-hsa-2476630, and piR-hsa-2834636 from blood small extracellular vesicles were identified as novel biomarkers for PD diagnosis using a sparse partial least square discriminant analysis (sPLS-DA) (accuracy: 92%, AUC = 0.89). This study highlights a role for piRNAs in PD and provides tools for novel biomarker development.