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

Sci Rep. 2015 Nov 26:5:17042. doi: 10.1038/srep17042.

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 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 γ-secretase complex formation. These data support that catalytically inactive PS1(∆exon8) is generated physiologically and participates in protein-protein interactions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / genetics
  • Animals
  • Brain / metabolism
  • Embryo, Mammalian / metabolism
  • Endoplasmic Reticulum / metabolism
  • Exons / genetics*
  • Fluorescence
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Membrane Glycoproteins / metabolism*
  • Mice, Knockout
  • Motor Activity
  • Phenotype
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Presenilin-1 / deficiency
  • Presenilin-1 / genetics*
  • Presenilin-1 / metabolism
  • Protein Binding
  • Sequence Deletion / genetics
  • Transgenes

Substances

  • Amyloid beta-Peptides
  • Membrane Glycoproteins
  • Presenilin-1
  • nicastrin protein
  • Amyloid Precursor Protein Secretases