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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2023
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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. |
format | Online Article Text |
id | pubmed-10411568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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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