ArticleJournal of cellular and molecular medicine2018
Specificity of presenilin-1- and presenilin-2-dependent γ-secretases towards substrate processing.
Article in Journal of cellular and molecular medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- Ferroptosis and Alzheimer's disease: unraveling the molecular mechanisms and therapeutic opportunities.Frontiers in cell and developmental biology · 2026Review
- TDP43 is a newly identified substrate for PS1, enhancing the expression of APP following cleavage.Cell death discovery · 2025Article
- The curious case of a heterozygous loss-of-functionMolecular neurodegeneration advances · 2025Article
- Brain Iron Dyshomeostasis and Ferroptosis in Alzheimer's Disease Pathophysiology: Two Faces of the Same Coin.Aging and disease · 2024Review
- Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia.International journal of oncology · 2023Article
- Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations.Molecules (Basel, Switzerland) · 2023Article
- Article
- The Genomic Architecture of Hidradenitis Suppurativa-A Systematic Review.Frontiers in genetics · 2022Review
- Presenilin mutations and their impact on neuronal differentiation in Alzheimer's disease.Neural regeneration research · 2022Article
- Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.Frontiers in molecular neuroscience · 2022Review
- Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies.Molecular neurobiology · 2021Article
- How to Build and to Protect the Neuromuscular Junction: The Role of the Glial Cell Line-Derived Neurotrophic Factor.International journal of molecular sciences · 2020Review
- Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization.iScience · 2020Article
- Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.International journal of molecular sciences · 2020Article
- Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis.Scientific reports · 2020Article
- Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial Phenotypes.Frontiers in neuroscience · 2020Article
- Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment.Frontiers in pharmacology · 2020Review
- Individual and combined presenilin 1 and 2 knockouts reveal that both have highly overlapping functions in HEK293T cells.The Journal of biological chemistry · 2019Article
- Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1.RSC advances · 2019Article
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The two presenilin-1 (PS1) and presenilin-2 (PS2) homologs are the catalytic core of the γ-secretase complex, which has a major role in cell fate decision and Alzheimer's disease (AD) progression. Understanding the precise contribution of PS1- and PS2-dependent γ-secretases to the production of β-amyloid peptide (Aβ) from amyloid precursor protein (APP) remains an important challenge to design molecules efficiently modulating Aβ release without affecting the processing of other γ-secretase substrates. To that end, we studied PS1- and PS2-dependent substrate processing in murine cells lacking presenilins (PSs) (PS1KO, PS2KO or PS1-PS2 double-KO noted PSdKO) or stably re-expressing human PS1 or PS2 in an endogenous PS-null (PSdKO) background. We characterized the processing of APP and Notch on both endogenous and exogenous substrates, and we investigated the effect of pharmacological inhibitors targeting the PSs activity (DAPT and L-685,458). We found that murine PS1 γ-secretase plays a predominant role in APP and Notch processing when compared to murine PS2 γ-secretase. The inhibitors blocked more efficiently murine PS2- than murine PS1-dependent processing. Human PSs, especially human PS1, expression in a PS-null background efficiently restored APP and Notch processing. Strikingly, and contrary to the results obtained on murine PSs, pharmacological inhibitors appear to preferentially target human PS1- than human PS2-dependent γ-secretase activity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.