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bioRxiv · 10.1101/2020.11.21.392761

Frameshift and frame-preserving mutations in zebrafish presenilin 2 affect different cellular functions in young adult brains

Barthelson, K.·Pederson, S. M.·Newman, M.·Jiang, H.·Lardelli, M.
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Abstract

BackgroundMutations in PRESENILIN 2 (PSEN2) cause early disease onset familial Alzheimers disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon - the "reading frame preservation rule". Mutations that do not obey this rule do not cause the disease. The reasons for this are debated. MethodsA frameshift mutation (psen2N140fs) and a reading frame-preserving mutation (psen2T141_L142delinsMISLISV) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analysed. Bioinformatics techniques were used to predict cellular functions affected by heterozygosity for each mutation. ResultsThe reading frame preserving mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signalling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions. ConclusionA frameshift and frame-preserving mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.

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Barthelson, K., Pederson, S. M., Newman, M., Jiang, H., Lardelli, M.. 2020-11-22. Frameshift and frame-preserving mutations in zebrafish presenilin 2 affect different cellular functions in young adult brains. https://doi.org/10.1101/2020.11.21.392761

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