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Here, we discovered that genetic mutations, introducing a premature termination codon (PTC) in the amyloid precursor protein-b (<jats:italic>appb<\/jats:italic>) gene, activated TA of two other<jats:italic>app<\/jats:italic>family members,<jats:italic>appa<\/jats:italic>and amyloid precursor-like protein-2 (<jats:italic>aplp2<\/jats:italic>), in zebrafish. The observed transcriptional response of<jats:italic>appa<\/jats:italic>and<jats:italic>aplp2<\/jats:italic>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<jats:italic>appa<\/jats:italic>,<jats:italic>appb<\/jats:italic>,<jats:italic>aplp1<\/jats:italic>, and<jats:italic>aplp2<\/jats:italic>. In conclusion, our results suggest that the expression level of App family members is regulated by the NMD pathway and that mutations destabilizing<jats:italic>app<\/jats:italic>\/<jats:italic>APP<\/jats:italic>mRNA can induce genetic compensation by other family members through TA in both zebrafish and human neuronal progenitors.<\/jats:p>","DOI":"10.1523\/eneuro.0034-24.2024","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T18:00:10Z","timestamp":1716573610000},"page":"ENEURO.0034-24.2024","source":"Crossref","is-referenced-by-count":3,"title":["Fine-Tuning Amyloid Precursor Protein Expression through Nonsense-Mediated mRNA 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