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NOS1AP is a novel molecular target and critical factor in TDP-43 pathology
Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins whic...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576154/ https://www.ncbi.nlm.nih.gov/pubmed/36267332 http://dx.doi.org/10.1093/braincomms/fcac242 |
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author | Cappelli, Sara Spalloni, Alida Feiguin, Fabian Visani, Giulia Šušnjar, Urša Brown, Anna-Leigh De Bardi, Marco Borsellino, Giovanna Secrier, Maria Phatnani, Hemali Romano, Maurizio Fratta, Pietro Longone, Patrizia Buratti, Emanuele |
author_facet | Cappelli, Sara Spalloni, Alida Feiguin, Fabian Visani, Giulia Šušnjar, Urša Brown, Anna-Leigh De Bardi, Marco Borsellino, Giovanna Secrier, Maria Phatnani, Hemali Romano, Maurizio Fratta, Pietro Longone, Patrizia Buratti, Emanuele |
author_sort | Cappelli, Sara |
collection | PubMed |
description | Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins which have been previously shown to regulate TAR DNA-binding protein 43 kDa toxicity (deleted in azoospermia-associated protein 1, heterogeneous nuclear ribonucleoprotein -Q, -D, -K and -U). Using the transcriptome analyses, we have uncovered that Nitric Oxide Synthase 1 Adaptor Protein mRNA is a direct TAR DNA-binding protein 43 kDa target, and in flies, its modulation alone can rescue TAR DNA-binding protein 43 kDa pathology. In primary mouse cortical neurons, we show that TAR DNA-binding protein 43 kDa mediated downregulation of Nitric Oxide Synthase 1 Adaptor Protein expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of Nitric Oxide Synthase 1 Adaptor Protein mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic Stathmin-2 and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that Nitric Oxide Synthase 1 Adaptor Protein may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies. |
format | Online Article Text |
id | pubmed-9576154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-95761542022-10-19 NOS1AP is a novel molecular target and critical factor in TDP-43 pathology Cappelli, Sara Spalloni, Alida Feiguin, Fabian Visani, Giulia Šušnjar, Urša Brown, Anna-Leigh De Bardi, Marco Borsellino, Giovanna Secrier, Maria Phatnani, Hemali Romano, Maurizio Fratta, Pietro Longone, Patrizia Buratti, Emanuele Brain Commun Original Article Many lines of evidence have highlighted the role played by heterogeneous nuclear ribonucleoproteins in amyotrophic lateral sclerosis. In this study, we have aimed to identify transcripts co-regulated by TAR DNA-binding protein 43 kDa and highly conserved heterogeneous nuclear ribonucleoproteins which have been previously shown to regulate TAR DNA-binding protein 43 kDa toxicity (deleted in azoospermia-associated protein 1, heterogeneous nuclear ribonucleoprotein -Q, -D, -K and -U). Using the transcriptome analyses, we have uncovered that Nitric Oxide Synthase 1 Adaptor Protein mRNA is a direct TAR DNA-binding protein 43 kDa target, and in flies, its modulation alone can rescue TAR DNA-binding protein 43 kDa pathology. In primary mouse cortical neurons, we show that TAR DNA-binding protein 43 kDa mediated downregulation of Nitric Oxide Synthase 1 Adaptor Protein expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of Nitric Oxide Synthase 1 Adaptor Protein mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic Stathmin-2 and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that Nitric Oxide Synthase 1 Adaptor Protein may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies. Oxford University Press 2022-09-23 /pmc/articles/PMC9576154/ /pubmed/36267332 http://dx.doi.org/10.1093/braincomms/fcac242 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Cappelli, Sara Spalloni, Alida Feiguin, Fabian Visani, Giulia Šušnjar, Urša Brown, Anna-Leigh De Bardi, Marco Borsellino, Giovanna Secrier, Maria Phatnani, Hemali Romano, Maurizio Fratta, Pietro Longone, Patrizia Buratti, Emanuele NOS1AP is a novel molecular target and critical factor in TDP-43 pathology |
title | NOS1AP is a novel molecular target and critical factor in TDP-43 pathology |
title_full | NOS1AP is a novel molecular target and critical factor in TDP-43 pathology |
title_fullStr | NOS1AP is a novel molecular target and critical factor in TDP-43 pathology |
title_full_unstemmed | NOS1AP is a novel molecular target and critical factor in TDP-43 pathology |
title_short | NOS1AP is a novel molecular target and critical factor in TDP-43 pathology |
title_sort | nos1ap is a novel molecular target and critical factor in tdp-43 pathology |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576154/ https://www.ncbi.nlm.nih.gov/pubmed/36267332 http://dx.doi.org/10.1093/braincomms/fcac242 |
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