TY - JOUR
T1 - NOS1AP is a novel molecular target and critical factor in TDP-43 pathology
AU - NYGC ALS Consortium
AU - Cappelli, Sara
AU - Spalloni, Alida
AU - Feiguin, Fabian
AU - Visani, Giulia
AU - Šušnjar, Urša
AU - Brown, Anna Leigh
AU - De Bardi, Marco
AU - Borsellino, Giovanna
AU - Secrier, Maria
AU - Phatnani, Hemali
AU - Romano, Maurizio
AU - Fratta, Pietro
AU - Longone, Patrizia
AU - Buratti, Emanuele
AU - Phatnani, Hemali
AU - Kwan, Justin
AU - Sareen, Dhruv
AU - Broach, James R.
AU - Simmons, Zachary
AU - Arcila-Londono, Ximena
AU - Lee, Edward B.
AU - Van Deerlin, Vivianna M.
AU - Shneider, Neil A.
AU - Fraenkel, Ernest
AU - Ostrow, Lyle W.
AU - Baas, Frank
AU - Zaitlen, Noah
AU - Berry, James D.
AU - Malaspina, Andrea
AU - Fratta, Pietro
AU - Cox, Gregory A.
AU - Thompson, Leslie M.
AU - Finkbeiner, Steve
AU - Dardiotis, Efthimios
AU - Miller, Timothy M.
AU - Chandran, Siddharthan
AU - Pal, Suvankar
AU - Hornstein, Eran
AU - MacGowan, Daniel J.
AU - Heiman-Patterson, Terry
AU - Hammell, Molly G.
AU - Patsopoulos, Nikolaos A.
AU - Butovsky, Oleg
AU - Dubnau, Joshua
AU - Nath, Avindra
AU - Bowser, Robert
AU - Harms, Matt
AU - Aronica, Eleonora
AU - Poss, Mary
AU - Gotkine, Marc
N1 - Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - ALS
KW - CAPON/NOS1AP
KW - hnRNPs
KW - RNA stability
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=85144086117&partnerID=8YFLogxK
U2 - 10.1093/braincomms/fcac242
DO - 10.1093/braincomms/fcac242
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AN - SCOPUS:85144086117
SN - 2632-1297
VL - 4
JO - Brain Communications
JF - Brain Communications
IS - 5
ER -