1. Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1.
- Author
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Rey F, Maghraby E, Messa L, Esposito L, Barzaghini B, Pandini C, Bordoni M, Gagliardi S, Diamanti L, Raimondi MT, Mazza M, Zuccotti G, Carelli S, and Cereda C
- Subjects
- Humans, beta Catenin metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Leukocytes, Mononuclear metabolism, Zinc Finger E-box-Binding Homeobox 1 genetics, Zinc Finger E-box-Binding Homeobox 1 metabolism, Amyotrophic Lateral Sclerosis genetics, MicroRNAs genetics, MicroRNAs metabolism, Neuroblastoma, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
Background: Deregulation of transcription in the pathogenesis of sporadic Amyotrophic Lateral Sclerosis (sALS) is taking central stage with RNA-sequencing analyses from sALS patients tissues highlighting numerous deregulated long non-coding RNAs (lncRNAs). The oncogenic lncRNA ZEB1-AS1 is strongly downregulated in peripheral blood mononuclear cells of sALS patients. In addition, in cancer-derived cell lines, ZEB1-AS1 belongs to a negative feedback loop regulation with hsa-miR-200c, acting as a molecular sponge for this miRNA. The role of the lncRNA ZEB1-AS1 in sALS pathogenesis has not been characterized yet, and its study could help identifying a possible disease-modifying target., Methods: the implication of the ZEB1-AS1/ZEB1/hsa-miR-200c/BMI1 pathway was investigated in multiple patients-derived cellular models (patients-derived peripheral blood mononuclear cells and induced pluripotent stem cells-derived neural stem cells) and in the neuroblastoma cell line SH-SY5Y, where its function was inhibited via RNA interference. Molecular techniques such as Real Time PCR, Western Blot and Immunofluorescence were used to assess the pathway dysregulation., Results: Our results show a dysregulation of a signaling pathway involving ZEB1-AS1/hsa-miR-200c/β-Catenin in peripheral blood mononuclear cells and in induced pluripotent stem cells-derived neural stem cells from sALS patients. These results were validated in vitro on the cell line SH-SY5Y with silenced expression of ZEB1-AS1. Moreover, we found an increase for ZEB1-AS1 during neural differentiation with an aberrant expression of β-Catenin, highlighting also its aggregation and possible impact on neurite length., Conclusions: Our results support and describe the role of ZEB1-AS1 pathway in sALS and specifically in neuronal differentiation, suggesting that an impairment of β-Catenin signaling and an alteration of the neuronal phenotype are taking place., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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