Transcriptome analysis indicates dominant effects on ribosome and mitochondrial function of a premature termination codon mutation in the zebrafish gene<i>psen2</i>

Dong

et al. 2021

Preprint

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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.

Section: Discussionsupporting

confidence: 54%

Section: Analysis Of Mouse Brain Transcriptomes Is Complicated By Strmentioning

confidence: 99%

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

Dong

et al. 2021

Preprint

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“…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, 26, 44].…”

Section: Discussionmentioning

confidence: 91%

“…We term this experimental strategy Be tween S ibling T ranscriptome (BeST) analysis. We have previously performed BeST analyses for EOfAD-like mutations in psen1 [15] and sorl1 [16, 17] and for a complex (but possibly EOfAD-like) mutation in psen2 : psen2 S4Ter [18].…”

Section: Introductionmentioning

confidence: 99%

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

Pederson

et al. 2020

Preprint

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BackgroundMutations in PRESENILIN 2 (PSEN2) cause early disease onset familial Alzheimer’s 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.

“…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, 2021; Barthelson et al, 2020b; Barthelson et al, 2020c; Barthelson et al, 2020e; 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.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

Lardelli

2021

Preprint

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Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains, Here we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early onset familial Alzheimer's disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain's energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models of APOE alleles and found the same effect for the late onset Alzheimer's disease risk allele E4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer's disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.