Dysregulation of MicroRNAs and PIWI-Interacting RNAs in a Caenorhabditis elegans Parkinson's Disease Model Overexpressing Human α-Synuclein and Influence of tdp-1

MicroRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) regulate gene expression and biological processes through specific genetic and epigenetic mechanisms. Recent studies have described a dysregulation of small non-coding RNAs in Parkinson's disease (PD) tissues but have been limited in scope. Here, we extend these studies by comparing the dysregulation of both miRNAs and piRNAs from transgenic Caenorhabditis elegans (C. elegans) nematodes overexpressing pan-neuronally human alpha-synuclein wild-type (WT) (HASN(WT) OX) or mutant (HASN(A53T) OX). We observed 32 miRNAs and 112 piRNAs dysregulated in HASN(A53T) OX compared with WT. Genetic crosses of HASN(A53T) OX PD animal models with tdp-1 null mutants, the C. elegans ortholog of TDP-43, an RNA-binding protein aggregated in frontal temporal lobar degeneration, improved their behavioral deficits and changed the number of dysregulated miRNAs to 11 and piRNAs to none. Neuronal function-related genes T28F4.5, C34F6.1, C05C10.3, camt-1, and F54D10.3 were predicted to be targeted by cel-miR-1018, cel-miR-355-5p (C34F6.1 and C05C10.3), cel-miR-800-3p, and 21ur-1581 accordingly. This study provides a molecular landscape of small non-coding RNA dysregulation in an animal model that provides insight into the epigenetic changes, molecular processes, and interactions that occur during PD-associated neurodegenerative disorders.

Automated summary

MicroRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) were found to be dysregulated in Parkinson's disease (PD) tissues. When comparing miRNA and piRNA dysregulation in transgenic C. elegans nematodes overexpressing human alpha-synuclein wild-type (WT) or mutant A53T, genetic crosses with tdp-1 null mutants improved behavioral deficits and altered the number of dysregulated miRNAs and piRNAs. Prediction of target genes by specific miRNAs shed light on the molecular landscape of small non-coding RNA dysregulation in PD-associated neurodegenerative disorders.