Author:
Jiang Haowei,Newman Morgan,Lardelli Michael
Abstract
AbstractAlzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, (hereafter “N140fs”), causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, (hereafter “T141_L142delinsMISLISV”), that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame. Both mutations are homozygous viable although N140fs transcripts are subject to nonsense-mediated decay and lack any possibility of coding for an active γ-secretase enzyme. N140fs homozygous larvae initially show grossly normal melanotic skin pigmentation but subsequently lose this as they grow while retaining pigmentation in the retinal pigmented epithelium. T141_L142delinsMISLISV homozygotes retain faint skin melanotic pigmentation as adults, most likely indicating that the protein encoded by this allele retains weak γ-secretase activity. Null mutations in the human PRESENILIN genes do not cause Alzheimer’s disease so these two mutations may be useful for future investigation of the differential effects of null and fAD-like PRESENILIN mutations on brain aging.Financial Disclosure StatementThis research was supported by grants from the National Health and Medical Research Council of Australia, GNT1061006 and GNT1126422, and by funds from the School of Biological Sciences of the University of Adelaide. HJ is supported by an Adelaide Scholarship International from the University of Adelaide.Conflict of Interest StatementThe authors declare no conflict of interest.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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