- The unfolded protein response: a common pathomechanism in tauopathies
- Award date
- 5 October 2012
- Number of pages
- Oisterwijk: Boxpress
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
In this thesis we demonstrate that the UPR is an early event in tauopathies that lies upstream of tau pathology. Therefore, in vivo models of tauopathies, in which mutant tau is overexpressed, bypass this important early step of UPR activation. It is thus pivotal to identify the initial inducer of ER stress in the tauopathy brain. Interestingly, diabetes is a risk factor for developing AD, the major tauopathy. Glucose deprivation is a known inducer of the UPR and a disruption in insulin signalling and glucose metabolism in the brain may trigger ER stress. Regional reductions in brain glucose metabolism are apparent in MCI and in AD, thus linking reduced brain metabolism to pathology. Furthermore, ischemia and traumatic brain have been shown to activate the UPR in animal models. In tauopathies it is unknown whether ER stress is caused by a transient stress inducer, after which neurons are inadequate at restoring ER homeostasis and the UPR is not switched off, or whether ER stress is caused by a continuous disruption of ER homeostasis.
Much is known about the signalling of the separate arms of the UPR, however little is known about the timing of their activation or whether cell specific modulation of the UPR occurs. It is important to further dissect the involvement of selective pathways of the UPR, to determine whether a specific signalling route of the UPR is responsible for tau phosphorylation. This may be achieved with drugs like Salubrinal or constructs that express active UPR components and transcription factors. This will facilitate the development of selective UPR modulating drugs that may be implemented for the treatment of tauopathies.
- Research conducted at: Universiteit van Amsterdam
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