The understanding of the dynamics of microtubules and the role of their protein partners that regulate the cytoskeleton remains incomplete. A better knowledge will enlighten fundamental processes of critical importance in biology (cell cycle, neurobiology). Indeed, increasing evidence show that minor alteration of cytoskeleton dynamics is accompanied by major cellular effects, as demonstrated on the cell cycle and transport in neurons, which opens perspective sin medicine (cancer, neurodegenerative diseases). Studying the role of spastin on neuronal microtubule cytoskeleton and deciphering its functions related to the bidirectional transport of vesicles and mRNA. Understanding how tubulin/microtubule targeting agents may relief neuron abnormalities observed in spastin KO mice (which mimic human spastin paraplegia).
i. Exploring the molecular mechanisms of the axonopathy associated to spastin mutation. Studying the interaction of Tau with microtubules at the molecular level and its role on the spatial organization and microtubule bundle dynamics in axons. Investigating the role of Tau on spastin-mediated microtubule cleavage on microtubules and the role of RNA:Tau interaction in Tau misorting both aspect being relevant aspects of synapse loss or dendritic spine shortening in Alzheimer’s diseases.
ii. Studying molecular aspects of the regulation of the cytoskeleton dynamics. This will concern the structure-function relationships of tubulin partners notably based on molecular modeling and using NMR as a tool; the study of the impact of small natural molecules on the cytoskeleton. Development and screening of such molecules will in turn be achieved by Synsight.