NOS1AP is a novel molecular target and critical factor in TDP-43 pathology

• Published in: Brain communications Vol. 4; no. 5; p. fcac242
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2022
• Subjects: Original; ALS; RNA stability; hnRNPs; TDP-43; CAPON/NOS1AP
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcac242

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 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 expression strongly affects the NMDA-receptor signalling pathway. In human patients, the downregulation of mRNA strongly correlates with TAR DNA-binding protein 43 kDa proteinopathy as measured by cryptic and Unc-13 homolog A cryptic exon inclusion. Overall, our results demonstrate that may represent a novel disease-relevant gene, potentially suitable for the development of new therapeutic strategies.