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Changes to energy metabolism, and signal transduction (i.e. Notch and Wnt signalling) define the brain transcriptomic differences between mutations causative for early-onset familial Alzheimer’s disease or familial acne inversa in PRESENILIN 1

ABSTRACT: Background: Mutations in PRESENILIN 1 (PSEN1) which still produce a transcript encoding a full-length, but mutant protein are the most common cause of early-onset familial Alzheimer’s disease (EOfAD). The only frameshift mutations found in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutations, and how they lead to completely different diseases, remains largely unexplored. Objective: To identify the similarities and differences of the effects of heterozygosity for mutations in psen1 causing EOfAD (T428del) or fAI (W233fs) on the brain transcriptome of young adult zebrafish. Methods: RNA sequencing was performed with high read depth on mRNA isolated from the brains of young adult (6 month old) zebrafish arising from a single family which contained either a single, heterozygous EOfAD-like or fAI-like mutation in the endogenous psen1 gene, and their wild type siblings. Results: Both mutations appeared to downregulate genes encoding the ribosomal subunits, and upregulated genes involved in inflammation. Genes involved in energy metabolism appeared to only be affected in EOfAD-like mutants, while genes involved in Notch, Wnt and neutrophin signalling pathways were only significantly altered by the fAI-like mutation. Further investigation of direct transcriptional targets of Notch revealed an apparent increase in Notch signalling. Conclusion: We observed both common, and distinct effects on transcriptomes of the heterozygous mutants compared to their wild type siblings. The distinct effects observed may shed light to how these mutations give rise to completely different diseases.

ORGANISM(S): Danio rerio

PROVIDER: GSE164466 | GEO | 2021/02/01

REPOSITORIES: GEO

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Project description:Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed a transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed Goseq analysis and gene set enrichment analysis (GSEA). This predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Extracellular matrix (ECM) related genes were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3’ untranslated regions. These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.

Project description:To prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in sorl1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains, comparing wild type fish with their siblings heterozygous for EOfAD-like or putatively loss-of-function mutations in sorl1, or transheterozygous for these mutations. Differential gene expression analysis identified a small number of differentially expressed genes due to the sorl1 genotypes. We also performed enrichment analysis on all detectable genes to obtain a more complete view on changes to gene expression by performing three methods of gene set enrichment analysis, then calculated an overall significance value using the harmonic mean p-value. This identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to sorl1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type sorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.

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Changes to energy metabolism, and signal transduction (i.e. Notch and Wnt signalling) define the brain transcriptomic differences between mutations causative for early-onset familial Alzheimer’s disease or familial acne inversa in PRESENILIN 1

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