This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie COFUND grant agreement No 665735.

Bio4Med Research Projects:

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8: Bio4Med - Molecular basis of tauopathies: Role of prion protein and other cellular cofactors

prof. Krzysztof Nieznanski
Foreign partner:
Prof. Witold K. Surewicz School of Medicine, Case Western Reserve University, Cleveland, USA
Background: Tau is a cytoskeletal protein responsible for stabilization of axonal microtubules. Oligomerization of Tau and accumulation of Tau amyloid aggregates in the brain is one of the hallmarks of a number of neurodegenerative diseases including Alzheimer’s disease, sporadic corticobasal degeneration, progressive supranuclear palsy, Pick's disease, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17. Neurotoxic oligomers and aggregates of Tau are secreted by affected neurons and may cause spread of Tau pathology in the brain by a prion-like mechanism. Interestingly, it has been demonstrated that monomeric Tau interacts directly with a normal (cellular) form of the prion protein (PrPC). Furthermore, co-deposition of aggregates of the pathogenic form of the prion protein (PrPSc) and hyperphosphorylated Tau has been frequently reported in prion diseases, pointing to a potential role of PrP in tauopathies. This is consistent with our recent observations that PrPC binds to amyloid aggregates of Tau. Our working hypothesis is that PrPC and other cellular cofactors may influence neurodegenerative process in tauopathies. Methodology: This project will employ a combination of biochemical, biophysical and cell biological approaches. Recombinant fragments and deletion variants of Tau and PrP will be expressed and purified, and their binding properties/affinities will be analyzed by pull-down assays, cross-linking, surface plasmon resonance and electron paramagnetic resonance spectroscopy. Aggregation of Tau will be monitored by Thioflavin T fluorescence as well as transmission electron and atomic force microscopy. Cytotoxicity assays for Tau oligomers/aggregates will be performed in rat primary culture of neurons and synaptotoxicity of these aggregates will be tested by long-term potentiation measurements in hippocampal brain slices.
The project is aimed at understanding the role of PrP and other cellular cofactors in the pathogenesis of tauopathies. This insight may provide a basis for novel therapeutic strategies in these fatal neurodegenerative diseases.
We are seeking a highly motivated individual who is enthusiastic about biomedical research and has strong background in molecular biology (cloning, mutagenesis, etc.) and protein biochemistry. An additional advantage will be an experience in cell biology or neurophysiology methods. Candidates must not have resided or carried out their main activity (work, studies, etc.) in Poland for more than 12 months in the past 3 years.