Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1
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 d...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612300044X |
| _version_ | 1828034759599587328 |
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| author | Federica Rey Erika Maghraby Letizia Messa Letizia Esposito Bianca Barzaghini Cecilia Pandini Matteo Bordoni Stella Gagliardi Luca Diamanti Manuela Teresa Raimondi Massimiliano Mazza Gianvincenzo Zuccotti Stephana Carelli Cristina Cereda |
| author_facet | Federica Rey Erika Maghraby Letizia Messa Letizia Esposito Bianca Barzaghini Cecilia Pandini Matteo Bordoni Stella Gagliardi Luca Diamanti Manuela Teresa Raimondi Massimiliano Mazza Gianvincenzo Zuccotti Stephana Carelli Cristina Cereda |
| author_sort | Federica Rey |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T15:37:11Z |
| format | Article |
| id | doaj.art-e812b5a222174b5ea09e7bc4979c1ff2 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-10T15:37:11Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e812b5a222174b5ea09e7bc4979c1ff22023-02-13T04:06:58ZengElsevierNeurobiology of Disease1095-953X2023-03-01178106030Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1Federica Rey0Erika Maghraby1Letizia Messa2Letizia Esposito3Bianca Barzaghini4Cecilia Pandini5Matteo Bordoni6Stella Gagliardi7Luca Diamanti8Manuela Teresa Raimondi9Massimiliano Mazza10Gianvincenzo Zuccotti11Stephana Carelli12Cristina Cereda13Pediatric Research Center ''Romeo ed Enrica Invernizzi'', Department of Biomedical and Clinical Sciences, University of Milan, Milan, ItalyPediatric Research Center ''Romeo ed Enrica Invernizzi'', Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, ItalyCenter of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy; Department of Electronics, Information and Bioengineering (DEIB), Politecnico di Milano, Milan, ItalyPediatric Research Center ''Romeo ed Enrica Invernizzi'', Department of Biomedical and Clinical Sciences, University of Milan, Milan, ItalyDepartment of Chemistry, Materials and Chemical Engineering ''Giulio Natta'', Politecnico di Milano, Milan, ItalyDepartment of Biosciences, University of Milan, Milan, ItalyCellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Pavia, ItalyMolecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, Pavia, ItalyNeuroncology Unit, IRCCS Mondino Foundation, Pavia, ItalyDepartment of Chemistry, Materials and Chemical Engineering ''Giulio Natta'', Politecnico di Milano, Milan, ItalyImmunotherapy, Cell Therapy and Biobank (ITCB), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyPediatric Research Center ''Romeo ed Enrica Invernizzi'', Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; Department of Pediatrics, Buzzi Children's Hospital, Milan, ItalyPediatric Research Center ''Romeo ed Enrica Invernizzi'', Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; Corresponding author at: Pediatric Clinical Research Center Fondazione “Romeo ed Enrica Invernizzi”, Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children's Hospital, Milan, ItalyBackground: 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.http://www.sciencedirect.com/science/article/pii/S096999612300044XZEB1-AS1hsa-miR-200cLong non-coding RNAAmyotrophic Lateral SclerosiscancerNeurodegeneration |
| spellingShingle | Federica Rey Erika Maghraby Letizia Messa Letizia Esposito Bianca Barzaghini Cecilia Pandini Matteo Bordoni Stella Gagliardi Luca Diamanti Manuela Teresa Raimondi Massimiliano Mazza Gianvincenzo Zuccotti Stephana Carelli Cristina Cereda Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1 Neurobiology of Disease ZEB1-AS1 hsa-miR-200c Long non-coding RNA Amyotrophic Lateral Sclerosis cancer Neurodegeneration |
| title | Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1 |
| title_full | Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1 |
| title_fullStr | Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1 |
| title_full_unstemmed | Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1 |
| title_short | Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1 |
| title_sort | identification of a novel pathway in sporadic amyotrophic lateral sclerosis mediated by the long non coding rna zeb1 as1 |
| topic | ZEB1-AS1 hsa-miR-200c Long non-coding RNA Amyotrophic Lateral Sclerosis cancer Neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S096999612300044X |
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