Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds

Abstract

Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant early onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis.Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56 years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long Aβ peptides and enhances the production of Aβ43, which has been shown to be potently amyloidogenic and neurotoxic in vivo.

Pathogenic PSEN1 Glu184Gly Mutation in a Family from Thailand with Probable Autosomal Dominant Early Onset Alzheimer’s Disease

“…PSEN1 Gly183Val revealed in skipping exon 6 or both exon 6-7, resulting in reduced PSEN1 function [31]. PSEN1 Ser290Cys was located at the splice junction of exon 8 and 10, causing deletion of entire exon 9 [32,33]. Additional mutations indicated significant impacts on PSEN1 mRNA splicing, such as Leu113Pro [34], Leu113Gln [35], Glu184Gly [19], Glu184Asp [24], and Arg377Trp [19].…”

Beneficial Effect of a Selective Adenosine A2A Receptor Antagonist in the APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

“…Aβ length is under the control of the carboxypeptidase activity of the gamma-secretase which cleaves the Aβ peptide from its carboxy-terminal region. Thus, lack of PS1 exon 9 and exon 10 generates longer Aβ peptides (Le Guennec et al, 2017 ). Although speculative, MSX3 could promote the carboxypeptidase activity of the gamma-secretase and thus modify the ratio of Aβ towards the production of shorter species of Aβ peptides.…”

Transcriptomics in Alzheimer’s Disease: Aspects and Challenges

“…Mutations/variants in PSEN1, located near the 5 and 3 may eliminate the acceptor or donor splicing site, and result in exon skipping. One of the most known splice site mutations in PSEN1 is the deletion of exon 9 (Ser290Cys) or exon 9 -10 (Ser290Trp), associated with aggressive AD phenotypes [66,67]. Additional exon-skipping mutations were also described, which could result in abnormal splicings, such as Leu113_I114insTyr [68], Leu271Val [69], or Ile416Thr [70].…”