Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress

Accumulation of unfolded/misfolded proteins in neuronal cells perturbs endoplasmic reticulum homeostasis, triggering a stress cascade called unfolded protein response (UPR), markers of which are upregulated in Alzheimer’s disease (AD) brain specimens. We measured the UPR dynamic response in three hu...

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Autores principales:	Ioanna C. Stefani, François-Xavier Blaudin de Thé, Cleo Kontoravdi, Karen M. Polizzi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	unfolded protein response amyloid precursor protein beta-amyloid mathematical modelling endoplasmic reticulum stress neurodegeneration Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/5a6cba5835624cd4a206738c6ed43383
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spelling	oai:doaj.org-article:5a6cba5835624cd4a206738c6ed433832021-11-11T17:24:52ZModel Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress10.3390/ijms2221120011422-00671661-6596https://doaj.org/article/5a6cba5835624cd4a206738c6ed433832021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12001https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Accumulation of unfolded/misfolded proteins in neuronal cells perturbs endoplasmic reticulum homeostasis, triggering a stress cascade called unfolded protein response (UPR), markers of which are upregulated in Alzheimer’s disease (AD) brain specimens. We measured the UPR dynamic response in three human neuroblastoma cell lines overexpressing the wild-type and two familial AD (FAD)-associated mutant forms of amyloid precursor protein (APP), the Swedish and Swedish-Indiana mutations, using gene expression analysis. The results reveal a differential response to subsequent environmental stress depending on the genetic background, with cells overexpressing the Swedish variant of APP exhibiting the highest global response. We further developed a dynamic mathematical model of the UPR that describes the activation of the three branches of this stress response in response to unfolded protein accumulation. Model-based analysis of the experimental data suggests that the mutant cell lines experienced a higher protein load and subsequent magnitude of transcriptional activation compared to the cells overexpressing wild-type APP, pointing to higher susceptibility of mutation-carrying cells to stress. The model was then used to understand the effect of therapeutic agents salubrinal, lithium, and valproate on signalling through different UPR branches. This study proposes a novel integrated platform to support the development of therapeutics for AD.Ioanna C. StefaniFrançois-Xavier Blaudin de ThéCleo KontoravdiKaren M. PolizziMDPI AGarticleunfolded protein responseamyloid precursor proteinbeta-amyloidmathematical modellingendoplasmic reticulum stressneurodegenerationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12001, p 12001 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	unfolded protein response amyloid precursor protein beta-amyloid mathematical modelling endoplasmic reticulum stress neurodegeneration Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	unfolded protein response amyloid precursor protein beta-amyloid mathematical modelling endoplasmic reticulum stress neurodegeneration Biology (General) QH301-705.5 Chemistry QD1-999 Ioanna C. Stefani François-Xavier Blaudin de Thé Cleo Kontoravdi Karen M. Polizzi Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress
description	Accumulation of unfolded/misfolded proteins in neuronal cells perturbs endoplasmic reticulum homeostasis, triggering a stress cascade called unfolded protein response (UPR), markers of which are upregulated in Alzheimer’s disease (AD) brain specimens. We measured the UPR dynamic response in three human neuroblastoma cell lines overexpressing the wild-type and two familial AD (FAD)-associated mutant forms of amyloid precursor protein (APP), the Swedish and Swedish-Indiana mutations, using gene expression analysis. The results reveal a differential response to subsequent environmental stress depending on the genetic background, with cells overexpressing the Swedish variant of APP exhibiting the highest global response. We further developed a dynamic mathematical model of the UPR that describes the activation of the three branches of this stress response in response to unfolded protein accumulation. Model-based analysis of the experimental data suggests that the mutant cell lines experienced a higher protein load and subsequent magnitude of transcriptional activation compared to the cells overexpressing wild-type APP, pointing to higher susceptibility of mutation-carrying cells to stress. The model was then used to understand the effect of therapeutic agents salubrinal, lithium, and valproate on signalling through different UPR branches. This study proposes a novel integrated platform to support the development of therapeutics for AD.
format	article
author	Ioanna C. Stefani François-Xavier Blaudin de Thé Cleo Kontoravdi Karen M. Polizzi
author_facet	Ioanna C. Stefani François-Xavier Blaudin de Thé Cleo Kontoravdi Karen M. Polizzi
author_sort	Ioanna C. Stefani
title	Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress
title_short	Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress
title_full	Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress
title_fullStr	Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress
title_full_unstemmed	Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress
title_sort	model identifies genetic predisposition of alzheimer’s disease as key decider in cell susceptibility to stress
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5a6cba5835624cd4a206738c6ed43383
work_keys_str_mv	AT ioannacstefani modelidentifiesgeneticpredispositionofalzheimersdiseaseaskeydeciderincellsusceptibilitytostress AT francoisxavierblaudindethe modelidentifiesgeneticpredispositionofalzheimersdiseaseaskeydeciderincellsusceptibilitytostress AT cleokontoravdi modelidentifiesgeneticpredispositionofalzheimersdiseaseaskeydeciderincellsusceptibilitytostress AT karenmpolizzi modelidentifiesgeneticpredispositionofalzheimersdiseaseaskeydeciderincellsusceptibilitytostress
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Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress

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