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- Title
Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1−/− phenotype and forms complexes with wildtype PS1 and nicastrin.
- Authors
Brautigam, Hannah; Moreno, Cesar L.; Steele, John W.; Bogush, Alexey; Dickstein, Dara L.; Kwok, John B.J.; Schofield, Peter R.; Thinakaran, Gopal; Mathews, Paul M.; Hof, Patrick R.; Gandy, Sam; Ehrlich, Michelle E.
- Abstract
The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer's disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1∆exon8). We previously reported that PS1 L271V increased amyloid beta (Aβ) 42/40 ratios, while PS1∆exon8 reduced Aβ42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1∆exon8 did not rescue Aβ generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1∆exon8 is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1∆exon8 in vivo by crossing PS1∆exon8 transgenics with either PS1-null or Dutch APPE693Q mice. As a control, we crossed APPE693Q with mice expressing a deletion in an adjacent exon (PS1∆exon9). PS1∆exon8 did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1∆exon8 interacts with nicastrin, participating in the γ-secretase complex formation. These data support that catalytically inactive PS1∆exon8 is generated physiologically and participates in protein-protein interactions.
- Subjects
PRESENILINS; EXONS (Genetics); NICASTRIN; GENETICS of Alzheimer's disease; TRANSGENIC mice
- Publication
Scientific Reports, 2015, p17042
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/srep17042