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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/12001 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:00:39Z |
| format | Article |
| id | doaj.art-5a6cba5835624cd4a206738c6ed43383 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:00:39Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5a6cba5835624cd4a206738c6ed433832023-11-22T21:01:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122211200110.3390/ijms222112001Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to StressIoanna C. Stefani0François-Xavier Blaudin de Thé1Cleo Kontoravdi2Karen M. Polizzi3Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UKDepartment of Chemical Engineering, Imperial College London, London SW7 2AZ, UKDepartment of Chemical Engineering, Imperial College London, London SW7 2AZ, UKDepartment of Chemical Engineering, Imperial College London, London SW7 2AZ, UKAccumulation 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.https://www.mdpi.com/1422-0067/22/21/12001unfolded protein responseamyloid precursor proteinbeta-amyloidmathematical modellingendoplasmic reticulum stressneurodegeneration |
| spellingShingle | 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 International Journal of Molecular Sciences unfolded protein response amyloid precursor protein beta-amyloid mathematical modelling endoplasmic reticulum stress neurodegeneration |
| title | 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_short | 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 |
| topic | unfolded protein response amyloid precursor protein beta-amyloid mathematical modelling endoplasmic reticulum stress neurodegeneration |
| url | https://www.mdpi.com/1422-0067/22/21/12001 |
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