Fine-tuning amyloid precursor protein expression through non-sense mediated mRNA decay

Abstract

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 (hNPC), 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.

Significance statement Genetic variations increasing APP levels are associated with Alzheimer's disease (AD) pathophysiology. It is therefore of key interest to understand the mechanisms regulating APP expression levels. Here, we identify transcriptional adaptation as a mechanism by which members of the APP family can modulate the expression level of genes in the same family to compensate for the loss of another. Upon the introduction of a PTC, compensation is driven through factors in the NMD pathway mediating mRNA decay. Interestingly, our data also show that the NMD surveillance machinery is an important aspect of fine-tuning mRNA levels of APP family members even under physiological conditions. Our findings therefore provide insights into compensation between APP members and reveal new targets by which APP can be regulated.