Article ; Online: Rare A360T Mutation Alters GSK3β(Ser9) Binding in the Cytosolic Loop of Presenilin 1, Influencing β-Catenin Nuclear Localization and Pro-Death Gene Expression in Alzheimer's Disease Case.
International journal of molecular sciences
2023 Volume 24, Issue 23
Abstract: Presenilin 1 (PS1) forms, via its large cytosolic loop, a trimeric complex with N-cadherin and β-catenin, which is a key component of Wnt signaling. PS1 undergoes phosphorylation at 353 and 357 serines upon enhanced activity and elevated levels of the ... ...
| Abstract | Presenilin 1 (PS1) forms, via its large cytosolic loop, a trimeric complex with N-cadherin and β-catenin, which is a key component of Wnt signaling. PS1 undergoes phosphorylation at 353 and 357 serines upon enhanced activity and elevated levels of the GSK3β isoform. PS1 mutations surrounding these serines may alter the stability of the β-catenin complex. Such mutations are found in some cases of familial early-onset Alzheimer's disease (fEOAD), but their functional impact remains obscure. One of such variants of PS1, the A360T substitution, is located close to GSK3β-targeted serine residues. This variant was recently demonstrated in the French population, but more detail is needed to understand its biological effects. To assess the significance of this variant, we employed functional studies using a fibroblast cell line from an Alzheimer's disease case (a female proband) carrying the A360T mutation. Based on functional transcriptomic, cellular, and biochemical assays, we demonstrated atypically impaired β-catenin/GSK3β signaling in the A360T patient's fibroblasts. In detail, this was characterized by a decreased level of active cytosolic β-catenin and bound by PS1, an increased level of nuclear β-catenin, an increased level of inhibited GSK3β phosphorylated on Ser9, and enhanced interaction of GSK3β(Ser9) with PS1. Based on the transcriptomic profile of the A360T fibroblasts, we proposed a dysregulated transcriptional activity of β-catenin, exemplified by increased expression of various cyclin-dependent kinases and cyclins, such as cyclin D1, potentially inducing neurons' cell cycle re-entry followed by apoptosis. The A360T cells did not exhibit significant amyloid pathology. Therefore, cell death in this PS1 cytosolic loop mutation may be attributed to impaired β-catenin/GSK3β signaling rather than amyloid deposition per se. We further estimated the biological and clinical relevance of the A360T variant by whole exome sequencing (WES). WES was performed on DNA from the blood of an A360T female proband, as well as an unrelated male patient carrying the A360T mutation and his mutation-free daughter (both unavailable for the derivation of the fibroblast cell lines). WES confirmed the highest-priority AD causality of the A360T variant in PS1 and also profiled the pathways and processes involved in the A360T case, highlighting the greatest importance of altered Wnt signaling. |
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| MeSH term(s) | Female ; Male ; Humans ; beta Catenin/genetics ; Alzheimer Disease/genetics ; Glycogen Synthase Kinase 3 beta/genetics ; Trans-Activators/genetics ; Presenilin-1/genetics ; Mutation ; Gene Expression |
| Chemical Substances | beta Catenin ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Trans-Activators ; Presenilin-1 |
| Language | English |
| Publishing date | 2023-11-30 |
| Publishing country | Switzerland |
| Document type | Case Reports |
| ZDB-ID | 2019364-6 |
| ISSN | 1422-0067 ; 1422-0067 ; 1661-6596 |
| ISSN (online) | 1422-0067 |
| ISSN | 1422-0067 ; 1661-6596 |
| DOI | 10.3390/ijms242316999 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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