Descripción del proyecto
Conformación de la proteína tau como diana terapéutica para la enfermedad de Alzheimer
Las proteínas tau se encuentran en abundancia en las neuronas del sistema nervioso central y se expresan en concentraciones muy bajas en los astrocitos y los oligodentrocitos, ocupándose de la estabilización de los microtúbulos. Las taupatías, incluida la enfermedad de Alzheimer, se asocian con cambios conformacionales durante la oligomerización y el ensamblaje, lo que ocasiona toxicidad celular. La proteína tau alterada desde el punto de vista conformacional podría ser una diana molecular prometedora para la terapia modificadora de la enfermedad. El objetivo principal del proyecto financiado con fondos europeos InterTAU es estudiar la estructura detallada de las proteínas tau y sus variantes en estados monoméricos, oligoméricos y fibrilares pertinentes para las enfermedades. El consorcio internacional InterTAU incluye una empresa de biotecnología en fase clínica que se dedica al desarrollo de una inmunoterapia antitau, así como socios del mundo académico con metodologías adecuadas para la caracterización funcional y estructural de la vía de modificación de tau mediante resonancia magnética nuclear, microscopía crioelectrónica y ensayos celulares.
Objetivo
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.
Ámbito científico
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepathology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesmolecular biologystructural biology
Palabras clave
Programa(s)
Régimen de financiación
MSCA-RISE - Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE)Coordinador
601 77 Brno
Chequia