Table_12_Dysregulation of MicroRNAs and PIWI-Interacting RNAs in a Caenorhabditis elegans Parkinson’s Disease Model Overexpressing Human α-Synuclein and Influence of tdp-1.XLSX

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 α-synuclein wild-type (WT) (HASNWT OX) or mutant (HASNA53T OX). We observed 32 miRNAs and 112 piRNAs dysregulated in HASNA53T OX compared with WT. Genetic crosses of HASNA53T 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.

微小RNA（MicroRNAs, miRNAs）与PIWI互作RNA（PIWI-interacting RNAs, piRNAs）可通过特异性遗传与表观遗传机制调控基因表达及生物学过程。近期研究已报道帕金森病（Parkinson’s disease, PD）组织中小非编码RNA的表达失调，但相关研究范围较为局限。本研究拓展了前述工作，比较了神经元全域过表达野生型人α-突触核蛋白（HASNWT OX）或突变型人α-突触核蛋白（HASNA53T OX）的转基因秀丽隐杆线虫（Caenorhabditis elegans, C. elegans）中miRNAs与piRNAs的失调情况。相较于野生型组，我们在HASNA53T OX组中观测到32种miRNAs及112种piRNAs存在表达失调。将HASNA53T OX PD动物模型与tdp-1敲除突变体（tdp-1 null mutants）进行遗传杂交后发现，该突变体所携带的tdp-1基因是RNA结合蛋白TDP-43的秀丽隐杆线虫同源物，而TDP-43在额颞叶叶变性中会发生聚集；杂交后模型的行为缺陷得到改善，且失调的miRNAs数量降至11种，piRNAs则无失调表达。研究预测，神经元功能相关基因T28F4.5、C34F6.1、C05C10.3、camt-1及F54D10.3分别被cel-miR-1018、cel-miR-355-5p（靶向C34F6.1与C05C10.3）、cel-miR-800-3p及21ur-1581所调控。本研究绘制了PD相关神经退行性疾病动物模型中小非编码RNA表达失调的分子图谱，可为该类疾病中的表观遗传改变、分子过程及相互作用机制研究提供新的科学视角。