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Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1-/- phenotype and forms complexes with wildtype PS1 and nicastrin.


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 (A?) 42/40 ratios, while PS1(?exon8) reduced A?42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1(?exon8) did not rescue A? 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 APP(E693Q) mice. As a control, we crossed APP(E693Q) 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 ?-secretase complex formation. These data support that catalytically inactive PS1(?exon8) is generated physiologically and participates in protein-protein interactions.

SUBMITTER: Brautigam H 

PROVIDER: S-EPMC4660297 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1-/- phenotype and forms complexes with wildtype PS1 and nicastrin.

Brautigam Hannah H   Moreno Cesar L CL   Steele John W JW   Bogush Alexey A   Dickstein Dara L DL   Kwok John B J JB   Schofield Peter R PR   Thinakaran Gopal G   Mathews Paul M PM   Hof Patrick R PR   Gandy Sam S   Ehrlich Michelle E ME  

Scientific reports 20151126


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 A  ...[more]

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