ArticleThe Journal of biological chemistry2010
A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 89 citations in OpenAlex.
- Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like, Microenvironment.International journal of molecular sciences · 2026Article
- Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice.bioRxiv : the preprint server for biology · 2026Article
- Haploinsufficiency and Alzheimer's Disease: The Possible Pathogenic and Protective Genetic Factors.International journal of molecular sciences · 2024Review
- Cortical neurodegeneration caused byProceedings of the National Academy of Sciences of the United States of America · 2024Article
- The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Cell-autonomous role of leucine-rich repeat kinase in the protection of dopaminergic neuron survival.eLife · 2024Article
- Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function.International journal of molecular sciences · 2024Article
- Lipophorin receptors genetically modulate neurodegeneration caused by reduction of Psn expression in the aging Drosophila brain.Genetics · 2024Article
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration inProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Developing a Gene Therapy for the Treatment of Autosomal Dominant Alzheimer's Disease.Human gene therapy · 2023Article
- Aβ43 levels determine the onset of pathological amyloid deposition.The Journal of biological chemistry · 2023Article
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- Early Diagnosis of Alzheimer's Disease with Blood Test; Tempting but Challenging.International journal of molecular and cellular medicine · 2023Review
- Selective ferroptosis vulnerability due to familial Alzheimer's disease presenilin mutations.Cell death and differentiation · 2022Article
- Article
- A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase.Communications biology · 2022Article
- Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.Brain pathology (Zurich, Switzerland) · 2022Article
- Amyloid β (Aβ) ELISA of Human iPSC-Derived Neuronal Cultures.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation.Translational psychiatry · 2021Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in presenilin-1 and presenilin-2 (PS1 and PS2) are the most common cause of familial Alzheimer disease. PS1 and PS2 are the presumptive catalytic components of the multisubunit gamma-secretase complex, which proteolyzes a number of type I transmembrane proteins, including the amyloid precursor protein (APP) and Notch. APP processing by gamma-secretase produces beta-amyloid peptides (Abeta40 and Abeta42) that accumulate in the Alzheimer disease brain. Here we identify a pathogenic L435F mutation in PS1 in two affected siblings with early-onset familial Alzheimer disease characterized by deposition of cerebral cotton wool plaques. The L435F mutation resides in a conserved C-terminal PAL sequence implicated in active site conformation and catalytic activity. The impact of PS1 mutations in and around the PAL motif on gamma-secretase activity was assessed by expression of mutant PS1 in mouse embryo fibroblasts lacking endogenous PS1 and PS2. Surprisingly, the L435F mutation caused a nearly complete loss of gamma-secretase activity, including >90% reductions in the generation of Abeta40, Abeta42, and the APP and Notch intracellular domains. Two nonpathogenic PS1 mutations, P433L and L435R, caused essentially complete loss of gamma-secretase activity, whereas two previously identified pathogenic PS1 mutations, P436Q and P436S, caused partial loss of function with substantial reductions in production of Abeta40, Abeta42, and the APP and Notch intracellular domains. These results argue against overproduction of Abeta42 as an essential property of presenilin proteins bearing pathogenic mutations. Rather, our findings provide support for the hypothesis that pathogenic mutations cause a general loss of presenilin function.
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