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

Abstract

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 <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) nematodes overexpressing pan-neuronally human α-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 <i>tdp-1</i> null mutants, the <i>C. elegans</i> 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 <i>T28F4.5</i>, <i>C34F6.1</i>, <i>C05C10.3</i>, <i>camt-1</i>, and <i>F54D10.3</i> were predicted to be targeted by cel-miR-1018, cel-miR-355-5p (<i>C34F6.1</i> and <i>C05C10.3</i>), 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.