Description du projet
Détermination de la structure des agrégats de protéines dans la maladie d’Alzheimer
La maladie d’Alzheimer (MA) est une maladie neurodégénérative progressive touchant principalement la population âgée. Elle se caractérise par l’accumulation d’agrégats de protéines bêta-amyloïdes et tau dans les cellules neuronales. Malgré leur neurotoxicité confirmée, ces oligomères protéiques n’ont pas été structurellement caractérisés en détail. La portée du projet Oligomers-MAS-NMR, financé par l’UE, est de déterminer la structure et l’interaction des oligomères bêta-amyloïdes et tau à l’aide de technologies de pointe. Les résultats du projet fourniront des connaissances fondamentales sur le mauvais repliement et l’agrégation des protéines dans la MA, ouvrant de nouvelles possibilités pour la conception de nouvelles stratégies de traitement.
Objectif
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder responsible for about 2 million deaths per year. Despite tremendous progress in basic research within the last years, its efficient treatment and diagnostic tools are still lacking. The previous studies have gathered sufficient evidence of a causative role of the aggregates of two proteins - amyloid beta and tau - in the AD pathogenesis. Both of these proteins can form highly toxic oligomeric species, which are the primary suspects of AD-related neurotoxicity. However, due to experimental difficulties the detailed structural and functional characterization of the oligomeric forms has been a big challenge. In the proposed project we aim to build on cutting-edge technologies and novel approaches to obtain atomic-level structures and investigate interactions of the amyloid beta and tau oligomers. Thus, this multidisciplinary project will apply (I) cell-free protein expression and purification protocols for incorporation of various selectively 13C, 15N and 19F labeled amino-acids; (II) microfluidics in order to generate size-controlled oligomers (III) solid-state NMR (ssNMR) at fast magic-angle spinning (MAS) regime tailored for 1H and 19F detection schemes. The anticipated outcome of this will be a unique combination of approaches to study amyloid aggregates, which can be further used and adapted for studying other protein assemblies. The project results will form the basis of innovation in the treatment of AD as well as other tauopathies.
Champ scientifique
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Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
LV-1006 Riga
Lettonie