Periodic Reporting for period 1 - InterTAU (Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease modifying drugs)
Reporting period: 2020-01-01 to 2023-06-30
Monitoring of conformation changes within the Tau protein variants that leads to its pathological forms characteristic in Alzheimer’s disease.
The detailed characterization of conformational changes of Tau protein towards its pathological forms will provide the basis for novel diagnostic and therapeutic strategies against Alzheimer’s disease involving Tau protein.
There are two overall project objectives:
i) To delineate pathways underlying pathologic tau polymerization, taking advantage of synergy created by the multidisciplinary InterTau network
ii) To establish a collaborative structure-characterizing platform on the basis of existing and newly created tools to identify innovative interventional and diagnostics targets in the tau assembly cascade
The detailed characterization of conformational changes of Tau protein towards its pathological forms will provide the basis for novel diagnostic and therapeutic strategies against Alzheimer’s disease involving Tau protein.
There are two overall project objectives:
i) To delineate pathways underlying pathologic tau polymerization, taking advantage of synergy created by the multidisciplinary InterTau network
ii) To establish a collaborative structure-characterizing platform on the basis of existing and newly created tools to identify innovative interventional and diagnostics targets in the tau assembly cascade
Within the InterTau consortium, we focused on the structural elucidation within the Tau protein in its monomeric and fibrillary form. In particular, the impact of different phosphorylations and truncations was studied. We have optimized the production of sufficient amounts of recombinant Tau, its fragments, and their different phosphorylated variants in high purity. It included also the production of isotopically labeled Tau variants. Subsequently, the Tau samples were analyzed by solution NMR spectroscopy where we managed to obtain almost complete assignment by applying the advance non-uniformly sampled methods. This NMR assignment will be used in the second half of InterTau project for the characterization of the binding epitopes towards the selected binding proteins. In terms of Tau fibrils the partial solid state NMR assignment was obtained that allowed us to characterize the differences in the Tau fibrilization and their formation initiated by seeding particles from truncated Tau. The results of such collaborative research were summarized in the form of the manuscript (doi: 10.1101/2023.02.01.526268) authored by three involved InterTau institutions (LIOS, INSAS, and MU) and is currently under revision. Similarly, researchers from these institutions published a review paper about NMR studies of Tau protein in tauopathies (doi: 10.3389/fmolb.2021.761227). The impact of different external factors, such as buffer conditions, on Tau fibrils formation has been monitored by atomic force microscopy and cryo-electron microscopy. These results are currently summarized within another collaborative manuscript.
The formed InterTau consortium significantly strengthens the collaboration between the involved institutions that include both academic institutions as well as biotech companies. It allows the intense flow of know-how between them and also allows the students and young scientists to experience the biotech environment and consider their future carrier in the commercial sector. Summer school organized within the InterTau project also allowed very valuable experience for the participating students.
The established collaborations within the Rise mobility InterTau project initiated another successful consortium project Horizont Europa: Excellence Hubs: HORIZON-WIDERA-2022-ACCESS-04 (ID: 101087124, period: 2023-2026): Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe that involves 4 institutions from the InterTau project (academic: MU, INSAS; industrial: BioVendor, Geneton). Jozef Hritz is also main coordinator in this new ADDIT-CE project and greatly benefitted from the obtained experiences by coordinating the InterTau project. ADDIT-CE project also involves Czech and Slovak Alzheimer’s Societies that will communicate the outcomes of both projects ADDIT-CE and InterTau to the general public.
The established collaborations within the Rise mobility InterTau project initiated another successful consortium project Horizont Europa: Excellence Hubs: HORIZON-WIDERA-2022-ACCESS-04 (ID: 101087124, period: 2023-2026): Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe that involves 4 institutions from the InterTau project (academic: MU, INSAS; industrial: BioVendor, Geneton). Jozef Hritz is also main coordinator in this new ADDIT-CE project and greatly benefitted from the obtained experiences by coordinating the InterTau project. ADDIT-CE project also involves Czech and Slovak Alzheimer’s Societies that will communicate the outcomes of both projects ADDIT-CE and InterTau to the general public.