Correlation Engine 2.0
Clear Search sequence regions

  • alleles (2)
  • alu elements (1)
  • Amyloid (2)
  • brain (1)
  • cerebellum (1)
  • dementia (1)
  • disease and (1)
  • exon (2)
  • genes (1)
  • human (2)
  • intron (2)
  • isoform (1)
  • pathogenesis (1)
  • protein human (1)
  • protein precursor (2)
  • PSEN1 (8)
  • PSEN2 (15)
  • psen2 protein human (1)
  • rna (2)
  • suggests (1)
  • Sizes of these terms reflect their relevance to your search.

    Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail:


    Meredith M Course, Kathryn Gudsnuk, C Dirk Keene, Thomas D Bird, Suman Jayadev, Paul N Valdmanis. Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain : a journal of neurology. 2023 Feb 13;146(2):507-518

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 35949106

    View Full Text