Unravelling the progression of unfolded protein Rresponse in a model system of familial Alzheimer’s disease
File(s)
Author(s)
Stefani Chrysoula, Ioanna
Type
Thesis
Abstract
Alzheimer’s disease (AD) is the most common form of dementia disorders and, yet, there is no preventative or curative treatment. It is associated with the progressive loss of memory and cognition and clinically divided into sporadic and familial forms. Familial Alzheimer’s disease (FAD) has predominantly a genetic predisposition with inherited mutations in the amyloid-β precursor protein (APP) and presinilin genes, which promote APP processing through the amyloidogenic pathway. This results in the release of the Aβ peptide, a major neurotoxic agent in AD progression.
Accumulation of unfolded and misfolded disease-specific proteins (including Aβ and tau proteins) in neuronal cells perturbs endoplasmic reticulum (ER) homeostasis, leading to the onset of a cellular stress cascade called unfolded protein response (UPR), markers of which are upregulated in AD brain specimens. This suggests a possible role for ER stress in activation and the pathogenesis of AD.
The research aimed to investigate the dynamic response of the UPR in an experimental model system of the disease combined with a computational model. For this purpose human neuroblastoma cell lines overexpressing the wild-type (APPWT) and two mutant forms of APP (APPMUT) associated with FAD were generated. Gene expression analysis of UPR markers revealed that overexpression of APP induces preconditioning of ER stress in all cell lines but with a stronger response in FAD-associated mutants. The progression sequence of UPR in APPWT and APPMUT was investigated in a time-course manner following the application of chemical stress. The results revealed that APPMUT exhibited the highest global response to chemically induced stress with a similar pattern. A computational model of the mammalian UPR was then generated and used to understand the dynamics of UPR. The model was able to reproduce our experimental data, which included pre-existing genetic factors (mutations in APP-associated with FAD) and a mimic of environmental triggers (induction of stress) consequently triggering the stress response. It suggested a different protein load and magnitude of transcriptional activation upon stress among the three cell lines. This was followed by in silico case studies exploring the effect of drugs targeting different branches of the UPR.
This study proposes a novel multidisciplinary platform that could be further used for the development of therapeutics for AD. As the familial and sporadic form of the disease have similar neuropathological characteristics, drugs efficacious for FAD will also be beneficial for the most common form of AD.
Accumulation of unfolded and misfolded disease-specific proteins (including Aβ and tau proteins) in neuronal cells perturbs endoplasmic reticulum (ER) homeostasis, leading to the onset of a cellular stress cascade called unfolded protein response (UPR), markers of which are upregulated in AD brain specimens. This suggests a possible role for ER stress in activation and the pathogenesis of AD.
The research aimed to investigate the dynamic response of the UPR in an experimental model system of the disease combined with a computational model. For this purpose human neuroblastoma cell lines overexpressing the wild-type (APPWT) and two mutant forms of APP (APPMUT) associated with FAD were generated. Gene expression analysis of UPR markers revealed that overexpression of APP induces preconditioning of ER stress in all cell lines but with a stronger response in FAD-associated mutants. The progression sequence of UPR in APPWT and APPMUT was investigated in a time-course manner following the application of chemical stress. The results revealed that APPMUT exhibited the highest global response to chemically induced stress with a similar pattern. A computational model of the mammalian UPR was then generated and used to understand the dynamics of UPR. The model was able to reproduce our experimental data, which included pre-existing genetic factors (mutations in APP-associated with FAD) and a mimic of environmental triggers (induction of stress) consequently triggering the stress response. It suggested a different protein load and magnitude of transcriptional activation upon stress among the three cell lines. This was followed by in silico case studies exploring the effect of drugs targeting different branches of the UPR.
This study proposes a novel multidisciplinary platform that could be further used for the development of therapeutics for AD. As the familial and sporadic form of the disease have similar neuropathological characteristics, drugs efficacious for FAD will also be beneficial for the most common form of AD.
Version
Open Access
Date Issued
2014-10
Date Awarded
2015-05
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
License URL
Advisor
Kontoravdi, Cleo
Polizzi, Karen
Sponsor
Engineering and Physical Sciences Research Council
Publisher Department
Chemical Engineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)