Upregulated lncRNA small nucleolar RNA host gene 1 promotes 1-methyl-4-phenylpyridinium ion-induced cytotoxicity and reactive oxygen species production through miR-15b-5p/GSK3β axis in human dopaminergic SH-SY5Y cells.

Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been demonstrated to be upregulated and play a crucial role in the pathology of Parkinson's disease (PD). However, the exact role of SNHG1 and its underlying mechanisms in PD remains elusive. In this study, we found that SNHG1 and glycogen synthase kinase 3 beta (GSK3β) were upregulated, but miR-15b-5p was downregulated in 1-methyl-4-phenylpyridinium ion (MPP+ )-treated SH-SY5Y cells. The upregulation of SNHG1 enhanced MPP+ -induced cellular toxicity in SH-SY5Y cells, as shown by decreased cell viability, increased ROS production, and increased number of TdT-mediated dUTP Nick-End labeling-positive cells, accompanied with the upregulation of cleaved caspase 3 and elevation of cytochrome C release. Meanwhile, SNHG1 knockdown presented the converse effects. SNHG1 was demonstrated to interact with miR-15b-5p. Moreover, SNHG1 could attenuate the inhibitory effects of miR-15b-5p on MPP+ -induced cytotoxicity and production of ROS. Besides, GSK3β was identified as a direct target of miR-15b-5p. The inhibitory effects of SNHG1 knockdown or miR-15b-5p overexpression on MPP+ -induced cytotoxicity and reactive oxygen species (ROS) production were abrogated by upregulation of GSK3β. Taken together, these results demonstrate that upregulated lncRNA SNHG1 promotes MPP+ -induced cytotoxicity and ROS production through the miR-15b-5p/GSK3β axis in human dopaminergic SH-SY5Y cells, suggesting that SNHG1 may act as a potential therapeutic target for PD treatment in the future.

Xie N ，Qi J ，Li S ，Deng J ，Chen Y ，Lian Y ... -  《-》

LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells.

Numerous long non-coding RNAs (lncRNAs) have been identified as aberrantly expressed in Parkinson's disease (PD). However, limited knowledge is available concerning the roles of dysregulated lncRNAs and the underlying molecular regulatory mechanism in the pathological process of PD. In this study, we found that lncRNA small nucleolar RNA host gene 1 (SNHG1) and seven in absentia homolog 1 (SIAH1) were upregulated, but microRNA-15b-5p (miR-15b-5p) was downregulated in SH-SY5Y cells pretreated with MPP+, as well as in MPTP-induced mouse model of PD. Overexpression of SIAH1 enhanced cellular toxicity of α-synuclein in SH-SY5Y cells, as indicated by the reduction of cell viability and elevation of LDH release. The percentage of α-synuclein aggregate-positive cells and the number of α-synuclein aggregates per cell were increased in SH-SY5Y cells transfected with pcDNA-SIAH1, while decreased after transfection with short interfering RNA specific for SIAH1 (si-SIAH1). Bioinformatics and luciferase reporter assay revealed that SIAH1 was a direct target of miR-15b-5p. We also found that SNHG1 could directly bind to miR-15-5p and repress miR-15-5p expression. Upregulation of miR-15b-5p alleviated α-synuclein aggregation and apoptosis by targeting SIAH1 in SH-SY5Y cells overexpressing α-synuclein. Overexpression of SNHG1 enhanced, whereas SNHG1 knockdown inhibited α-synuclein aggregation and α-synuclein-induced apoptosis. Moreover, the neuroprotective effect of si-SNHG1 was abrogated by downregulation of miR-15b-5p. In summary, our data suggest that SNHG1, as a pathogenic factor, promotes α-synuclein aggregation and toxicity by targeting the miR-15b-5p/SIAH1 axis, contributing to a better understanding of the mechanisms of Lewy body formation and loss of dopaminergic neurons in PD.

Chen Y ，Lian YJ ，Ma YQ ，Wu CJ ，Zheng YK ，Xie NC ... -  《-》

SNHG1 promotes MPP(+)-induced cytotoxicity by regulating PTEN/AKT/mTOR signaling pathway in SH-SY5Y cells via sponging miR-153-3p.

Zhao J ，Geng L ，Chen Y ，Wu C ... -  《-》

Deficiency of NEAT1 prevented MPP(+)-induced inflammatory response, oxidative stress and apoptosis in dopaminergic SK-N-SH neuroblastoma cells via miR-1277-5p/ARHGAP26 axis.

Noncoding RNAs including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been documented to play prominent role in neurodegenerative diseases including Parkinson's disease (PD). This study intended to investigate the role of lncRNA nuclear enriched assembly transcript 1 (NEAT1) in MPP+-induced PD model in dopaminergic neuronblastoma SK-N-SH cells, as well as its mechanism through sponging miRNA (miR)-1277-5p. Real-time PCR and western blotting revealed that NEAT1 and ARHGAP26 were upregulated, and miR-1277-5p was downregulated in MPP+-treated SK-N-SH cells in a certain of concentration- and time- dependent manner. MPP+ induced apoptosis in SK-N-SH cells, as evidenced by decreased cell viability and Bcl-2 expression, and elevated apoptosis rate and levels of Bax and cleaved caspase-3, which were examined by MTT assay, flow cytometry and western blotting. Moreover, commercial assay kits indicated that inflammatory response and oxidative stress were provoked in response to MPP+, due to promoted contents of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, malondialdehyde, and lactate dehydrogenase, accompanied with suppressed superoxide dismutase and glutathione peroxidase levels. Notably, MPP+-induced apoptosis, inflammatory response and oxidative stress in SK-N-SH cells were mitigated by NEAT1 knockdown and/or miR-1277-5p overexpression. Moreover, silencing of miR-1277-5p could abrogate the suppression of NEAT1 deficiency on MPP+-induced cell injury. Similarly, upregulating miR-1277-5p-elicited neuroprotection in MPP+-induced SK-N-SH cells was reversed by ARHGAP26 restoration. Dual-luciferase reporter assay demonstrated a direct interaction between miR-1277-5p and NEAT1 or ARHGAP26. Collectively, NEAT1 upregulation might contribute to MPP+-induced neuron injury via NEAT1-miR-1277-5p-ARHGAP26 competing endogenous RNAs (ceRNAs) pathway.

Zhou S ，Zhang D ，Guo J ，Chen Z ，Chen Y ，Zhang J ... -  《-》

Long noncoding RNA small nucleolar RNA host gene 12/microRNA-138-5p/nuclear factor I/B regulates neuronal apoptosis, inflammatory response, and oxidative stress in Parkinson's disease.

Yan L ，Li L ，Lei J 《-》