LncRNA H19 diminishes dopaminergic neuron loss by mediating microRNA-301b-3p in Parkinson's disease via the HPRT1-mediated Wnt/β-catenin signaling pathway.

Jingjing Jiang,Min Bao,Xuanyu Piao,Jingbo Gao,Siying Hu

doi:10.18632/aging.102877

Abstract

Long non-coding RNAs (lncRNA) and microRNAs (miRNAs) are a subject of active investigation in neurodegenerative disorders including Parkinson’s disease (PD). We hypothesized a regulatory role of lncRNA H19 with involvement of hypoxanthine phosphoribosyltransferase 1 (HPRT1) in dopaminergic neuron loss in PD model mice obtained by 6-hydroxydopamine (6-OHDA) lesions. We predicted the differentially expressed genes and related mechanisms by microarray analysis. We measured the expression of tyrosine hydroxylase (TH) and proneural genes in the substantia nigra of lesioned mice before and after treatment with lentiviral oe-HPRT1, agomir-miR-301b-3p and inhibition of the Wnt/β-catenin pathway. We also evaluated the relationship among lncRNA H19, HPRT1 and miR-301b-3p as well as the Wnt/β-catenin signaling pathway in these mice. The obtained results predicted and further confirmed a low level of HPRT1 in lesioned mice. We found low expression of lncRNA H19 and showed that its forced overexpression regulated HPRT1 by binding to miR-301b-3p. The overexpression of HPRT1 increased TH expression and inhibited dopaminergic neuron loss via activating the Wnt/β-catenin pathway, as reflected by increased expressions of Nurr-1, Pitx-3, Ngn-2 and NeuroD1. Thus, overexpressed lncRNA H19 protects against dopaminergic neuron loss in this PD model through activating the Wnt/β-catenin pathway via impairing miR-301b-3p-targeted inhibition of HPRT1 expression.

Highlights

Parkinson’s disease (PD) is reported to be the commonest neurodegenerative disorder, plaguing approximately 1% of those aged above 65 years across the globe [1]
The results indicate that hypoxanthine phosphoribosyltransferase 1 (HPRT1) may be a key player in 6-OHDA mediated dopamine loss
PD is a neurodegenerative disorder closely associated with midbrain dopaminergic neuron loss in the substantia nigra pars compacta [27, 28]

Summary

Introduction

Parkinson’s disease (PD) is reported to be the commonest neurodegenerative disorder, plaguing approximately 1% of those aged above 65 years across the globe [1]. The pathological characteristics of PD include dopaminergic neuron loss in the substantia nigra as well as the accumulation of Lewy bodies composed of synaptic protein α-synuclein [2, 3]. Patients suffering from PD are greatly vulnerable to cognitive decline notably including executive deficits beginning at an early phase of the disease [4]. In addition to typical motor symptoms, PD patients manifest such neuropsychiatric symptoms as anxiety, depression and motivational deficits [5]. The dopamine replacement therapies can typically the alleviate motor symptoms, their efficacy declines with PD progression [6]. Neuroprotective therapies addressing non-motor and nondopaminergic aspects without provoking serious side effects are actively investigated [7]. Studies are required to better understand the molecular events of PD, and characterize the potential biomarkers and pathways for treatment [8]

Methods

Results

Conclusion