The UPR in the cell-to-cell spreading of tau pathology in dementia.
Projectomschrijving
Achtergrond
De meeste dementiepatiënten hebben klontjes van het eiwit tau in de hersenen. Dit onderzoek richt zich op een proces dat vooraf gaat aan de klontering, de UPR (Unfolded Protein Response). Dit is een reactie die hersencellen beschermt tegen schade. Maar als de UPR te lang actief is, wordt de klontering van tau in gang gezet, zoals in de hersenen van patiënten gebeurt. Tijdens het verloop van de ziekte krijgen steeds meer hersencellen een actieve UPR en tau klontering.
Doel
In dit project wordt onderzocht hoe de UPR en tau klontjes zich verspreiden door de hersenen. De moleculen die hierbij betrokken zijn, worden door hersencellen gemaakt in een vroeg stadium van de ziekte. Hierdoor kunnen ze worden gebruikt om eerder te bepalen of dit ziekteproces in de hersenen van een patiënt plaatsvindt. Daarnaast zullen de resultaten van het onderzoek inzicht geven in het verspreidingsmechanisme van de ziekte. Hierdoor ontstaan nieuwe mogelijkheden om het ziekteproces een halt toe te roepen.
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Samenvatting van de aanvraag
The microtubule associated protein tau plays an essential role in the pathogenesis and spreading of the disease pathology in by far the great majority of dementias. Tau is phosphorylated and forms aggregates in neurons, leading to neuronal dysfunction and neurodegeneration. We have previously shown that the Unfolded Protein Response (UPR) is activated in an early stage of these tauopathies, which include amongst others Alzheimer’s disease, Frontotemporal dementia and parkinsonism linked to chromosome 17, Tangle-predominant dementia, and Pick's disease. Our data show that UPR activation initiates the first steps leading to tau pathology, the phosphorylation and oligomerization of tau. Currently, an important unanswered question is how disease pathology spreads through the brain. Cell-to-cell transmission of tau pathology has been observed in different models. Recently also UPR activation was shown to be transmitted from cell-to-cell. We hypothesize that UPR signaling is involved in spreading of tau pathology and facilitates AD progression. Because essential parts of this process take place outside the cells it will be more readily amenable for diagnostic and therapeutic purposes. In this project we will explore an entirely novel insight on how tau pathology spreads and progresses throughout the brain. The aim of this study is to identify key factors and signalling pathways in UPR transmission towards early diagnosis and therapy of tauopathies. In this project we will address the following objectives: 1. The UPR signaling routes and transfer mechanism involved in UPR transmission. 2. The identity of the secreted protein and RNA factor(s) involved in UPR transmission. 3. The involvement of UPR transmission in the spreading of tau pathology. 4. The presence of newly identified UPR transmission signaling pathways and factors in patients with tau related dementia. This project brings together top quality researchers from different disciplines. The combined expertise of the consortium partners will be employed to investigate the role of the UPR in tau progression in neuronal cell models and patient material. We use state-of-the-art molecular and cell biological techniques, proteomics and miRNA profiling technology to identify key factors and signaling pathways involved in the transmission of the UPR and tau pathology. A private partner will develop stable tau oligomers, an important tool for this project and neurodegenerative research and diagnostics in general. Within the consortium unique collections of patient material (brain tissue, cerebrospinal fluid (CSF), blood) are available for validation of the results as well as to indicate the potential for translation in diagnostic and therapeutic follow-up studies. The results from this study provide the first step in the development of a new disease modifying drug therapy that prevents disease progression. In addition, based on the early involvement of UPR activation in pathology, identification of UPR transmission factor(s) in the extracellular space would provide a CSF or blood biomarker for early diagnosis. It is expected that patents arise from this project. The novelty and relevance of the project in combination with the high quality of the project group is likely to yield high impact papers. This is a fundamental project that explores an entirely novel approach to target these highly prevalent diseases. Implementation of the results from this project requires additional investments of time and resources. Therefore as part of the project, we invest significantly to increase knowledge about fundamental science among the general public, in particular those affected directly or indirectly by dementia. For this purpose an interactive video project will be developed and implemented by an interactive media company together with a patient organization for dementia. Patients and carers will be involved in the development of this project. Goal is to gain long-term support for early stage translational research by participating in studies, brain donations and financial contributions.