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

• Published in: Aging (Albany, NY.) Vol. 12; no. 10; pp. 8820 - 8836
• Main Authors: Jiang, Jingjing, Piao, Xuanyu, Hu, Siying, Gao, Jingbo, Bao, Min
• Format: Journal Article
• Language: English
• Published: United States Impact Journals 20.05.2020
• Subjects: Animals; Disease Models, Animal; Dopaminergic Neurons - cytology; Dopaminergic Neurons - metabolism; Hypoxanthine Phosphoribosyltransferase - metabolism; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Parkinson Disease - metabolism; Research Paper; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Substantia Nigra - chemistry; Substantia Nigra - metabolism; Substantia Nigra - pathology; Wnt Signaling Pathway - physiology; microRNA-301b-3p; dopaminergic neuron; long noncoding RNA H19; Parkinson’s disease; hypoxanthine phosphoribosyltransferase 1
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.102877

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 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 impairing miR-301b-3p-targeted inhibition of HPRT1 expression.