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The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system

Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aβ peptides, mostly as the soluble Aβ40 with fewer insoluble Aβ42 peptides. Rar...

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Autores principales: Swanson, Mark J, Lewis, Kelsey N, Carpenter, Robert, Whetzel, Alexis, Bae, Nancy S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411568/
https://www.ncbi.nlm.nih.gov/pubmed/36929840
http://dx.doi.org/10.1093/g3journal/jkad057
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author Swanson, Mark J
Lewis, Kelsey N
Carpenter, Robert
Whetzel, Alexis
Bae, Nancy S
author_facet Swanson, Mark J
Lewis, Kelsey N
Carpenter, Robert
Whetzel, Alexis
Bae, Nancy S
author_sort Swanson, Mark J
collection PubMed
description Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aβ peptides, mostly as the soluble Aβ40 with fewer insoluble Aβ42 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into Aβ peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAPɛ), a protein found in the subventricular zone of the brain. We have found that GFAPɛ interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAPɛ in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAPɛ and PS1. GFAPɛ coprecipitated with RAP1 from human cell extracts. RAP1, GFAPɛ, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the γ-secretase complex in Saccharomyces cerevisiae, RAP1 increased γ-secretase activity, and this was potentiated by GFAPɛ. Our studies are the first to connect RAP1 with an age-related disorder.
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spelling pubmed-104115682023-08-10 The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system Swanson, Mark J Lewis, Kelsey N Carpenter, Robert Whetzel, Alexis Bae, Nancy S G3 (Bethesda) Genetic Models of Rare Diseases Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aβ peptides, mostly as the soluble Aβ40 with fewer insoluble Aβ42 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into Aβ peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAPɛ), a protein found in the subventricular zone of the brain. We have found that GFAPɛ interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAPɛ in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAPɛ and PS1. GFAPɛ coprecipitated with RAP1 from human cell extracts. RAP1, GFAPɛ, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the γ-secretase complex in Saccharomyces cerevisiae, RAP1 increased γ-secretase activity, and this was potentiated by GFAPɛ. Our studies are the first to connect RAP1 with an age-related disorder. Oxford University Press 2023-03-17 /pmc/articles/PMC10411568/ /pubmed/36929840 http://dx.doi.org/10.1093/g3journal/jkad057 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genetic Models of Rare Diseases
Swanson, Mark J
Lewis, Kelsey N
Carpenter, Robert
Whetzel, Alexis
Bae, Nancy S
The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system
title The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system
title_full The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system
title_fullStr The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system
title_full_unstemmed The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system
title_short The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system
title_sort human rap1 and gfapɛ proteins increase γ-secretase activity in a yeast model system
topic Genetic Models of Rare Diseases
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411568/
https://www.ncbi.nlm.nih.gov/pubmed/36929840
http://dx.doi.org/10.1093/g3journal/jkad057
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