The long noncoding RNA HOTAIR promotes Parkinson’s disease by upregulating LRRK2 expression

Sheng Wang,Xuan Zhang,Tiebang Liu,Han Rong,Yuanyuan Guo

doi:10.18632/oncotarget.15511

Sheng Wang, Xuan Zhang + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.15511

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Journal: Oncotarget	Publication Date: Feb 19, 2017
Citations: 89	License type: cc-by

Affiliation: Shenzhen KangNing Hospital

Abstract

Long noncoding RNAs (lncRNAs) have emerged recently as a new class of genes that regulate cellular processes. HOTAIR (Hox transcript antisense intergenic RNA), an approximately 2.2 kb long noncoding RNA transcribed from the HOXC locus, is upregulated in various diseases. However, the role of HOTAIR in Parkinson's disease (PD) remains unclear. A mouse model of PD was developed by intraperitoneal injection of MPTP. The expression of HOTAIR and LRRK2 were detected in the PD mice and in human neuroblastoma cell lines SH-SY5Y pretreated with MPP+. The effect of HOTAIR on the expression of LRRK2 was examined in SH-SY5Y cells through overexpressing or knockdown of HOTAIR. MTT and flow cytometry assay were performed to measure the cell viability and apoptosis of SH-SY5Y cells. We found that HOTAIR was up-regulated in midbrain tissue of MTPT induced PD mice and in SH-SY5Y cells exposed to MPP+. With the presence of HOTAIR overexpression in SH-SY5Y cells, the expression of LRRK2 was increased compared with that in the control. HOTAIR knockdown showed a protective effect on the cell viability of SH-SY5Y cells pretreated with MPP+. HOTAIR knockdown provided protection against MPP+-induced DA neuronal apoptosis by repressing caspase 3 activity. The finding that HOTAIR promoted PD induced by MPTP could add our understanding of the molecular mechanisms in PD. These findings suggested that inhibition of HOTAIR levels is an effective disease-modifying strategy in PD.

Highlights

Parkinson’s disease (PD), a neurologic disorder featured by resting tremor, slowness of movements, dementia, gait disturbance and postural instability, holds the second largest patient group among the neurodegenerative diseases [1]
To confirm the dysregulation of HOTAIR and LRRK2 in Parkinson's disease (PD) mice, the levels of HOTAIR and LRRK2 expression in SH-SY5Y cells exposed to MPP+ was investigated
The qRT-PCR and western blot data showed that MPP+ induced the LRRK2 expression levels in cultured cells (Figure 2B and 2C), indicating that HOTAIR and LRRK2 might be correlated with the development of PD

Summary

Introduction

Parkinson’s disease (PD), a neurologic disorder featured by resting tremor, slowness of movements, dementia, gait disturbance and postural instability, holds the second largest patient group among the neurodegenerative diseases [1]. LncRNAs are RNA transcripts in length of 200 nucleotides (nt) to ~100 kilobases (kb) yet not functioning as protein synthesis template [6]. They holds cis- or transregulatory capabilities, and more than 1000 lncRNAs are highly conserved in mammalian genome [7,8]. Recent reports have implicated lncRNA deregulation could be one of the common features of various human diseases including AD, and deregulated lncRNAs may be utilized for AD diagnosis, prognosis or even work out to be potential therapeutic targets [13,14,15]. Increasing evidence has shown that HOTAIR (Hox transcript antisense intergenic RNA), an approximately 2.2 kb lncRNA transcribed from the HOXC locus, is upregulated in various diseases [16,17]

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