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

Linjing Shen,Garry Wong,Liang Chen,Changliang Wang

doi:10.3389/fnins.2021.600462

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 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.

Highlights

MicroRNAs and PIWI-interacting RNAs are well conserved small non-coding RNAs 21–23 or 24–31 nucleotides in length, respectively
To further evaluate the roles of DE-miRNAs/DE-PIWI-interacting RNA (piRNA) in neurodegenerative diseases, we explored the correlation between DE-miRNAs/DE-piRNAs target genes and human neurodegenerative diseases including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), multiple system atrophy (MSA), and Huntington’s disease (HD) based on the gene–disease associations from the DisGeNET database
We observed that the miRNA/piRNA expression was broadly and abundantly altered by HASNA53T human α-synuclein overexpressing pan-neuronally (OX), but not HASNWT OX

Summary

Introduction

MicroRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) are well conserved small non-coding RNAs 21–23 or 24–31 nucleotides in length, respectively. PiRNAs mainly function in the repression of transposons at transcriptional or posttranscriptional levels to safeguard the germline genome (Iwasaki et al, 2015; Ernst et al, 2017). The identification of miRNAs dysregulated in neurodegenerative diseases and construction of related animal models may aid in delineation of molecular mechanisms underlying their pathologic processes (Juzwik et al, 2019). Exploitation of these molecular pathways via precision therapy strategies for neurodegenerative diseases is well underway (Junn and Mouradian, 2012; Pereira et al, 2017; Nuzziello et al, 2019). PiRNAs are beginning to be appreciated as pathogenic factors and therapeutic targets for neurodegenerative diseases as well as miRNAs (Wakisaka and Imai, 2019)

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