Transcriptome analyses of 7-day-old zebrafish larvae possessing a familial Alzheimer’s disease-like mutation in psen1 indicate effects on oxidative phosphorylation, ECM and MCM functions, and iron homeostasis
- To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.. - The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.. - 1 Alzheimer ’ s Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia Full list of author information is available at the end of the article. - Moreover, zebrafish possess orthologs of the human genes mutated in EOfAD. - Therefore, zebrafish have the potential to model EOfAD mutations for the study of the molecular pathological processes of AD. - This mutation deletes 2 codons but maintains the open reading frame, leading to structural and hydrophilicity changes in the first lumenal loop of the translated protein. - of the mRNA expression levels contributed by each larva in the pool. - Three of the four genes were seen to be differentially expressed to a. - In the Hallmark pathway (Table 1), G2M_CHECKPOINT contains genes critical for cell division cycle progression, and E2F_TARGETS includes numerous genes that play essential rolls in the cell cycle and DNA replication [30]. - Therefore, the Goseq results of the Hallmark, KEGG and Wiki pathway analyses (Table 1) show significant changes in DNA. - Among the DE genes in these two categories, most are members of the mini- chromosome maintenance (MCM) protein family.. - Downregulation of the genes mcm2, mcm3, mcm4, mcm5, mcm6 and mcmbp and upregulation of the gene mcm7 were observed in the heterozygous mutant larvae.. - Similar to the pathway analyses, most of the GO terms showing significant enrichment for DE genes are related to the cell cycle and DNA replication. - Four of the significantly-changed KEGG pathways are illustrated in Fig. - Regulation of the MCM complex plays essential roles in both pathways.. - Dysregulation of the MCM complex would influence DNA replication and might cause replication stress lead- ing to genomic instability [37]. - ob- served less than 12% of cells as originating from the CNS [26] so the transcriptome effects of the EOfAD-like psen1 Q96_K97del mutation that we have observed are likely systemic. - Therefore, use of the psen1 Q96_K97del EOfAD-like mutation for discovery of AD-preventative drugs remains infeasible until a suitable biomarker can be identified.. - MCM complex dysregulation may drive DNA replication stress Comparison of the transcriptomes of pools of 7 dpf het- erozygous psen1 Q96_K97del mutant larvae to their wild type siblings revealed highly significant regulatory effects on genes involved with DNA replication and the cell cycle. - The complex is comprised of the protein products of six genes, MCM2–7 (Fig. - Our transcriptome analysis of the ef- fect of heterozygosity for the psen1 Q96_K97del mutation on 6-month-old zebrafish brains also observed implied effects on lysosomal acidification [17]. - Mitochondrial dysfunction is an early effect of the psen1 Q96_K97del mutation. - larvae, particularly with downregulation of the tfa and tfr1b genes required for importation of iron, supports that EOfAD mutations in PSEN1 disturb ferrous iron homeostasis. - The zebrafish genetic lines used in this study were bred as stocks within the zebrafish facility of the Alzheimer’s Disease Genetics Laboratory of the University of Adel- aide. - org/10.1186/s . - Results from analysis of the enrichment of Iron Responsive Element (IRE) gene sets in the transcriptome data.. - ML and SP are employees of the University of Adelaide. - No funding body played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.. - Trimmed RNA-seq reads were aligned to the Danio rerio genome Ensembl Release 96 (GRCz11) of the Ensembl Project, [79] (www.ensembl.org). - Gene Ontology gene sets were obtained from geneontology.org using the org.. - Hallmark [92] and KEGG [93] gene sets were ob- tained from the Molecular Signatures Database, MSigDB (http://www.gsea- msigdb.org/gsea/msigdb/collections.jsp), using the msigdbr package [94].. - Wiki pathway gene sets were obtained from WikiPathways (https://wikipathways.org) using the rWiKipathways R package [85]. - 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