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LncRNA HOTAIR promotes MPP+-induced neuronal injury in Parkinson’s disease by regulating the miR-874-5p/ATG10 axis

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons. Long non-coding RNAs (lncRNAs) play an important role in many neurological diseases, including PD. This study aimed to investigate the role of lncRNA HOX transcript antisense RNA (HOTAIR) in PD pathogenesis and its potential mechanism. SK-N-SH cells were exposed to 1-methyl-4-phenylpyridinium (MPP+) to mimic PD model in vitro. The levels of HOTAIR, miR-874-5p and autophagy-related 10 (ATG10) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell viability and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The expression of apoptosis-related proteins was measured by western blot. The levels of neuroinflammation-related factors were detected by enzyme-linked immunosorbent assay (ELISA). Commercial kits was used to monitor lactate dehydrogenase (LDH) activity, reactive oxygen (ROS) generation and superoxide dismutase (SOD) activity. The interaction among HOTAIR, miR-874-5p and ATG10 were verified by dual-luciferase reporter assay or RNA immunoprecipitation (RIP) assay. HOTAIR and ATG10 were up-regulated, and miR-874-5p was down-regulated in dose- and time-dependent manners in MPP+-treated SK-N-SH cells. HOTAIR knockdown reduced MPP+-induced neuronal damage. HOTAIR aggrandized MPP+-triggered neuronal injury by sponging miR-874-5p. Also, miR-874-5p attenuated MPP+-triggered neuronal damage by targeting ATG10. Moreover, HOTAIR regulated ATG10 expression via sponging miR-874-5p. HOTAIR promoted MPP+-induced neuronal injury via modulating the miR-874-5p/ATG10 axis in SK-N-SH cells.

SUBMITTER: Zhao J

PROVIDER: S-EPMC7527508 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundAt present, the treatment of intracerebral hemorrhage (ICH)-induced secondary brain injury (ISB) is limited, and the curative effect is not good. Long noncoding RNAs (lncRNAs) have been reported to play a role in ISB after ICH. We preliminarily monitored the induction effect of lncRNA-pseudopodium-enriched atypical kinase 1 (PEAK1) on neuronal cell apoptosis after ICH through our previous study and further experimental verification. However, the specific role and mechanism of lncRNA-PEAK1 in neuronal cell apoptosis after ICH have not been reported.MethodsICH cell models were established with hemin. Pro-inflammatory cytokines, cell proliferation, and apoptosis were evaluated by enzyme-linked immunosorbent assay, Cell Counting Kit-8 assay, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Moreover, lncRNA expression associated with apoptosis was confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological functions of lncRNA-PEAK1, miR-466i-5p, and caspase8 were conducted in vitro. Further, we used bioinformatics, a dual-luciferase reporter assay, and rescue experiments to understand the mechanisms of competitive endogenous RNAs.ResultsqRT-PCR revealed that lncRNA-PEAK1 was markedly upregulated in ICH cell models. LncRNA-PEAK1 knockdown decreased the interleukin-1β and tumor necrosis factor-alpha levels, promoted cell proliferation, weakened cell apoptosis, and downregulated the key molecular protein levels involved in the cell apoptosis pathway. Bioinformatics analysis and dual-luciferase reporter assay revealed that lncRNA bound to miR-466i-5p, and caspase 8 was a target of miR-466i-5p. The mechanistic analysis demonstrated that lncRNA-PEAK1/miR-466i-5p promoted neuronal cell apoptosis by activating the apoptosis pathway through caspase8 after ICH.ConclusionCollectively, our investigation identified that the lncRNA-PEAK1/miR-446i-5p/caspase8 axis is closely related to neuronal cell apoptosis after ICH. Additionally, lncRNA-PEAK1 may be a potential target for ICH intervention.

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LncRNA HOTAIR promotes MPP+-induced neuronal injury in Parkinson’s disease by regulating the miR-874-5p/ATG10 axis

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