Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells

Version 1 : Received: 20 February 2022 / Approved: 25 February 2022 / Online: 25 February 2022 (02:40:02 CET)

How to cite: Zohar, K.; Giladi, E.; Eliyahu, T.; Linial, M. Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells. Preprints 2022, 2022020320. https://doi.org/10.20944/preprints202202.0320.v1 Zohar, K.; Giladi, E.; Eliyahu, T.; Linial, M. Alteration in Long Noncoding RNAs in Response to Oxidative Stress and Ladostigil in SH-SY5Y Cells. Preprints 2022, 2022020320. https://doi.org/10.20944/preprints202202.0320.v1

Abstract

Microglia activation causes neuroinflammation, which is a hallmark of neurodegenerative disorders, brain injury, and aging. Ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, reduced microglial activation and enhanced brain functioning in elderly rats. In this study, we studied SH-SY5Y, a human neuroblastoma cell line, and tested viability in the presence of hydrogen peroxide and Sin1 (3-morpholinosydnonimine), which generates reactive oxygen and nitrogen species (ROS/RNS). Both stressors caused significant apoptosis and necrotic cell death that was attenuated by ladostigil. Our results from RNA-seq experiments show that long non-coding RNAs (lncRNAs) account for 30% of all transcripts in SH-SY5Y cells treated with Sin1 for 24 hours. Altogether, we identify 94 differently expressed lncRNAs in the presence of Sin1, including MALAT1, a highly expressed lncRNA with anti-inflammatory and anti-apoptotic functions. Additional activities of Sin-1 upregulated lncRNAs include redox homeostasis (e.g., MIAT, GABPB1-AS1), energy metabolism (HAND2-AS1), and neurodegeneration (e.g., MIAT, GABPB1-AS1, NEAT1). Four lncRNAs implicated as enhancers were significantly upregulated in cells exposed to Sin1 and ladostigil. Finally, we show that H2O2 and Sin1 increased the expression of DJ-1, a redox sensor and modulator of Nrf2 (nuclear factor erythroid 2–related factor 2). Nrf2 (NFE2L2 gene) is a major transcription factor regulating antioxidant genes. In the presence of ladostigil, DJ-1 expression is restored to its baseline. The mechanisms governing SH-SY5Y cell survival and homeostasis are highlighted by the beneficial role of ladostigil in the crosstalk involving Nrf2, antioxidant transcription factor DJ-1, and lncRNAs. Stress-dependent induction of lncRNAs represents an underappreciated regulatory level that contributes to cellular homeostasis and the capacity of SH-SY5Y to cope with oxidative stress.

Keywords

Neurodegenerative disease; DJ-1; RNA-seq; Nrf2 signaling; lncRNA; MALAT1

Subject

Medicine and Pharmacology, Neuroscience and Neurology

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