Altering presenilin gene activity in zebrafish embryos causes changes in expression of genes with potential involvement in Alzheimer's disease pathogenesis.
Aberrant splicing and point mutations in the human presenilin genes, PSEN1 and PSEN2, have been linked to familial forms of Alzheimer's disease. We have previously described that low-level aberrant splicing of exon 8 in zebrafish psen1 transcripts in zebrafish embryos produces potent dominant negative effects that increase psen1 transcription, cause a dramatic hydrocephalus phenotype, decreased pigmentation and other developmental defects. Similar effects are also observed after low-level interference with splicing of exon 8 of psen2. To determine the molecular etiology of these effects, we performed microarray analyses of global gene expression changes. Of the 100 genes that showed greatest dysregulation after either psen1 or psen2 manipulation, 12 genes were common to both treatments. Five of these have known function and showed increased expression: cyclin G1 (ccng1), prosaposin (psap), cathepsin Lb (ctslb), heat shock protein 70kDa (hsp70) and hatching enzyme 1 (he1). We used phylogenetic and conserved synteny analysis to confirm the orthology of zebrafish ccng1 with human CCNG1. We analyzed the expression of zebrafish ccng1 in developing embryos to 24 hours post fertilization (hpf). Decreased ccng1 expression does not rescue the hydrocephalus or pigmentation phenotypes of embryos with aberrant splicing of psen1 exon 8.
Newman
Morgan
M
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, SA, Australia. morgan.newman@adelaide.edu.au
Tucker
Ben
B
Nornes
Svanhild
S
Ward
Alister
A
Lardelli
Michael
M
D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000502:physiology*; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology; D017403:In Situ Hybridization; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010802:Phylogeny; D010858:Pigmentation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2; D053763:Presenilins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000235:genetics*
C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D020320:Oligoribonucleotides, Antisense; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053763:Presenilins; D004247:DNA