Table_10_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（miRNA）和PIWI结合RNA（piRNA）通过特定的遗传和表观遗传机制调节基因表达及生物学过程。近期研究已描述了在帕金森病（PD）组织中小型非编码RNA的失调现象，但其研究范围有限。本研究在此基础上，通过比较过表达人类α-突触核蛋白野生型（WT）或突变型（HASNA53T）的转基因秀丽隐杆线虫（Caenorhabditis elegans）中miRNA和piRNA的失调情况，进一步扩展了相关研究。我们发现与WT相比，HASNA53T中失调的miRNA有32种，piRNA有112种。将HASNA53T PD动物模型与TDP-43（一种在额颞叶变性中聚集的RNA结合蛋白）的C. elegans同源基因tdp-1的突变体进行遗传杂交，改善了其行为缺陷，并将失调的miRNA数量减少至11种，piRNA数量降至无。预测与神经元功能相关基因T28F4.5、C34F6.1、C05C10.3、camt-1和F54D10.3相关的基因分别为cel-miR-1018、cel-miR-355-5p（C34F6.1和C05C10.3）、cel-miR-800-3p以及21ur-1581。本研究揭示了动物模型中小型非编码RNA失调的分子图谱，为理解帕金森病相关的神经退行性疾病的表观遗传变化、分子过程和相互作用提供了洞察。