Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease modifying drugs

ended

There is an enormous and unmet medical need to find efficient methods of prevention, diagnosis and disease- modifying therapies for neurodegenerative disorders, including Alzheimer’s disease (AD), other tauopathies and Parkinson’s disease (PD). The common molecular denominator of tauopathies are pathological forms of tau protein, and in Parkinson’s disease these are pathological forms of -synuclein. Moreover, -synuclein has a distinct role in pathophysiology of tauopathies, mainly in tau hyperphosphorylation and aggregation, and vice versa. Tau pathology relates to conformational changes during oligomerization and assembly resulting in toxicity. Given their role in the pathogenesis, conformationally altered and assembled tau or -synuclein would be a promising molecular target for disease-modifying therapies. However, the field is still lacking a deeper understanding of associated structural changes in the course of assembly and their inducers on the pathway towards pathological forms of these proteins; therefore, the pharma development is hampered. The main aim of the InterTau project is the detailed structural and biophysical characterization of tau and -synuclein -synuclein protein and their variants in monomeric, oligomeric and fibrillar states relevant for AD, other tauopathies. The InterTAU consortium is composed and academic partners with cutting- edge methodologies suitable for functional and structural characterization of the tau assembly pathway by solution and solid-state nuclear magnetic resonance (NMR), cryo-electron microscopy and cellular assays corroborated by bioinformatics. The mutual transfer of complementary expertise envisaged in the project will facilitate academic outcome and biotechnological development. Specific expertise will be transferred from three institutions in North America and one institution from Argentina. The results of InterTAU will be directly translated into innovation in biotech through the non-academic partner. The platform for sharing knowledge will be a foundation of sustainable cooperation beyond the InterTau project.