Alternative splicing in a presenilin 2 variant associated with Alzheimer disease

Abstract

Objective Autosomal‐dominant familial Alzheimer disease ( AD ) is caused by by variants in presenilin 1 ( PSEN 1 ), presenilin 2 ( PSEN 2 ), and amyloid precursor protein ( APP ). Previously, we reported a rare PSEN 2 frameshift variant in an early‐onset AD case ( PSEN 2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN 2 K115Efs*11 variant in two families. Results Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN 2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild‐type PSEN 2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN 2 K115Efs*11 fibroblasts secrete less A β 1–40 compared to controls, indicating abnormal γ ‐secretase activity. Analysis of PSEN 2 transcript levels in brain tissue revealed alternatively spliced PSEN 2 products in patient brain as well as in sporadic AD and age‐matched control brain. Interpretation These data suggest that PSEN 2 K115Efs*11 is a likely pathogenic variant associated with AD . We uncovered novel PSEN 2 alternative transcripts in addition to previously reported PSEN 2 splice isoforms associated with sporadic AD . In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.

RNA Dynamics in Alzheimer’s Disease

“…These genes form the catalytic domain of the gamma secretase complex, which is responsible for cleavage of APP [ 123 ]. Mutations in both genes are associated with familial AD [ 124 , 125 , 126 , 127 , 128 ]. In PSEN1 , at least four mutations have been described that produce aberrant splicing patterns [ 124 , 125 , 126 , 127 ].…”

Splicing alterations in healthy aging and disease

“…Finally, autosomal‐dominant familial Alzheimer's disease is caused by variants in presenilin 1 ( PSEN1 ), presenilin 2 ( PSEN2 ), and APP genes. Skipping of exons in PSEN1 or PSEN2 genes, which could lead to the expression of deleterious protein products, has been linked with the development of Alzheimer's disease (Braggin et al, 2019; De Jonghe et al, 1999; Love et al, 2015; Nornes et al, 2008; Sato et al, 1999). APP exon 7 containing isoforms, which are regulated by SF members of the RBFOX protein family (Alam et al, 2014), are elevated in brain tissue and can activate the intracellular domain of APP as well as beta secretase and could contribute to the accumulation of toxic β‐amyloid peptide (Belyaev et al, 2010).…”

Alterations in diabetes mellitus gene expression in the development and progression of Alzheimer's disease: The PI3K/Akt pathway link

“…Continuing with the alterations associated with the increase in production of Aβ is the genetic variants of both PSEN 1 and 2, which facilitate the processing of APPs by γ-secretase, which contributes to the formation of Aβ through the amyloidogenic pathway 9 .…”