ArticleThe Journal of biological chemistry2016
Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Glycogen synthase kinase-3: the master switch driving neurodegeneration in Alzheimer's disease and Parkinson's disease.Archives of toxicology · 2025Review
- The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system.G3 (Bethesda, Md.) · 2023Article
- Alzheimer's Disease: Significant Benefit from the Yeast-Based Models.International journal of molecular sciences · 2023Review
- Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production.International journal of molecular sciences · 2023Article
- Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Specific Mutations in Aph1 Cause γ-Secretase Activation.International journal of molecular sciences · 2022Article
- Rodent Models of Amyloid-Beta Feature of Alzheimer's Disease: Development and Potential Treatment Implications.Aging and disease · 2020Review
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- Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase is a multisubunit membrane protein complex containing presenilin (PS1) as a catalytic subunit. Familial Alzheimer disease (FAD) mutations within PS1 were analyzed in yeast cells artificially expressing membrane-bound substrate, amyloid precursor protein, or Notch fused to Gal4 transcriptional activator. The FAD mutations, L166P and G384A (Leu-166 to Pro and Gly-384 to Ala substitution, respectively), were loss-of-function in yeast. We identified five amino acid substitutions that suppress the FAD mutations. The cleavage of amyloid precursor protein or Notch was recovered by the secondary mutations. We also found that secondary mutations alone activated the γ-secretase activity. FAD mutants with suppressor mutations, L432M or S438P within TMD9 together with a missense mutation in the second or sixth loops, regained γ-secretase activity when introduced into presenilin null mouse fibroblasts. Notably, the cells with suppressor mutants produced a decreased amount of Aβ42, which is responsible for Alzheimer disease. These results indicate that the yeast system is useful to screen for mutations and chemicals that modulate γ-secretase activity.
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Registered trials
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.