RT Journal Article SR Electronic T1 Fine-Tuning Amyloid Precursor Protein Expression through Nonsense-Mediated mRNA Decay JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0034-24.2024 DO 10.1523/ENEURO.0034-24.2024 VO 11 IS 6 A1 Rahmati, Maryam A1 Chebli, Jasmine A1 Kumar Banote, Rakesh A1 Roselli, Sandra A1 Agholme, Lotta A1 Zetterberg, Henrik A1 Abramsson, Alexandra YR 2024 UL http://www.eneuro.org/content/11/6/ENEURO.0034-24.2024.abstract AB Studies on genetic robustness recently revealed transcriptional adaptation (TA) as a mechanism by which an organism can compensate for genetic mutations through activation of homologous genes. Here, we discovered that genetic mutations, introducing a premature termination codon (PTC) in the amyloid precursor protein-b (appb) gene, activated TA of two other app family members, appa and amyloid precursor-like protein-2 (aplp2), in zebrafish. The observed transcriptional response of appa and aplp2 required degradation of mutant mRNA and did not depend on Appb protein level. Furthermore, TA between amyloid precursor protein (APP) family members was observed in human neuronal progenitor cells; however, compensation was only present during early neuronal differentiation and could not be detected in a more differentiated neuronal stage or adult zebrafish brain. Using knockdown and chemical inhibition, we showed that nonsense-mediated mRNA decay (NMD) is involved in degradation of mutant mRNA and that Upf1 and Upf2, key proteins in the NMD pathway, regulate the endogenous transcript levels of appa, appb, aplp1, and aplp2. In conclusion, our results suggest that the expression level of App family members is regulated by the NMD pathway and that mutations destabilizing app/APP mRNA can induce genetic compensation by other family members through TA in both zebrafish and human neuronal progenitors.