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Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy
journal contributionposted on 2023-05-16, 14:40 authored by Kwok, JB, Halliday, GM, Brooks, WS, Dolios, G, Laudon, H, Murayama, O, Hallupp, M, Badenhop, RF, James VickersJames Vickers, Wang, R, Naslund, J, Takashima, A, Gandy, SE, Schofield, PR
The mutation L271V in exon 8 of the presenilin-1 (PS-i) gene was detected in an Alzheimer's disease pedigree. Neuropathological examination of affected individuals identified variant, large, non-cored plaques without neuritic dystrophy, reminiscent of cotton wool plaques. Biochemical analysis of L271V mutation showed that it increased secretion of the 42-amino acid amyloid-Î² peptide, suggesting a pathogenic mutation. Analysis of PS-1 transcripts from the brains of two mutation carriers revealed a 17-50% increase in PS-1 transcripts with deletion of exon 8 (PS-1Î”exon8) compared with unrelated Alzheimer's disease brains. Exon trapping analysis confirmed that L271V mutation enhanced the deletion of exon 8. Western blots of brain lysates indicated that PS-1Î”exon8 was overexpressed in an affected individual. Biochemical analysis of PS-1Î”exon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-Î². Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3Î² antibodies indicated that PS-1Î”exon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3Î², potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1Î”exon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.
Publication titleJournal of Biological Chemistry
Department/SchoolTasmanian School of Medicine
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc
Place of publicationBethesda, USA