Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy
journal contribution
posted on 2023-05-16, 14:40authored byKwok, 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-β 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-1Δexon8) 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-1Δexon8 was overexpressed in an affected individual. Biochemical analysis of PS-1Δexon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-β. Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3β antibodies indicated that PS-1Δexon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3β, potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1Δexon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.
History
Publication title
Journal of Biological Chemistry
Volume
278
Issue
9
Pagination
6748-6754
ISSN
0021-9258
Department/School
Tasmanian School of Medicine
Publisher
American Society for Biochemistry and Molecular Biology, Inc