PRESENILIN 1mutations causing early-onset familial Alzheimer’s disease or familial acne inversa differ in their effects on genes facilitating energy metabolism and signal transduction

Abstract

BackgroundThe most common cause of early-onset familial Alzheimer’s disease (EOfAD) is mutations in PRESENILIN 1 (PSEN1) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored.ObjectiveTo analyse brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity for psen1 mutations causing EOfAD or fAI.MethodsRNA sequencing was performed on mRNA isolated from the brains of a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenous psen1 gene.ResultsBoth mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signalling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signalling revealed possible increases in γ-secretase activity due to heterozygosity for either psen1 mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident.ConclusionWe observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases.

Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism

“…In our previously published analyses, we found that heterozygosity for most of our EOfAD-like mutations does not result in many differentially expressed (DE) genes in young adult brains (Barthelson et al, 2021a;Barthelson et al, 2021b;Barthelson et al, 2020b;Barthelson et al, 2021c;Newman et al, 2019) (as would be expected for modelling a disease that becomes overt in middle Disease Models & Mechanisms • DMM • Accepted manuscript age). Therefore, we performed gene set enrichment analyses to predict which cellular processes were affected by each of the mutations in each experiment.…”

“…Our group has exploited the zebrafish to generate a collection of knock-in models of EOfAD-like mutations in order to analyse their young brain transcriptomes (Barthelson et al, 2021a;Barthelson et al, 2021b;Barthelson et al, 2020b;Barthelson et al, 2021c;Dong et al, 2021;Hin et al, 2020a;Hin et al, 2020b;Jiang et al, 2020;Newman et al, 2019). Our experimental philosophy has been to replicate, as closely as possible, the single heterozygous mutation state of EOfAD in humans, thereby avoiding possibly misleading assumptions regarding the molecular mechanism(s) underlying the disease.…”

“…We first collated our findings from our zebrafish models of EOfAD-like mutations in psen1 (Barthelson et al, 2021a;Hin et al, 2020a;Hin et al, 2020b;Newman et al, 2019), psen2 (Barthelson et al, 2021b) and sorl1 (Barthelson et al, 2020b;Barthelson et al, 2021c). An advantage of using zebrafish for RNA-seq analyses is minimisation of genetic and environmental noise through breeding strategies such as that shown in Fig.…”

In-Frame and Frameshift Mutations in Zebrafish Presenilin 2 Affect Different Cellular Functions in Young Adult Brains

“…The second “hit” of this hypothesis is oxidative stress, which is an anticipated outcome of disturbance of oxidative phosphorylation. Notably, the EOfAD-like mutation of psen2 is predicted to affect oxidative phosphorylation, which is in common with all the other EOfAD-like mutations of genes we have examined in zebrafish [ 16, 18–22 ].…”

“…We term this experimental strategy Between Sibling Transcriptome (BeST) analysis. We have previously performed BeST analyses for EOfAD-like mutations in psen1 [ 16–19 ] and sorl1 [ 20, 21 ] and for a complex (but possibly EOfAD-like) mutation in psen2 : psen2 S 4 Ter [ 22 ].…”