Research will be focused on the structure and function of two macromolecular assemblies critical for physiopathology based on the following background:
i) Dynamics of the microtubule cytoskeleton
Microtubules play a major role in neurons which are highly asymmetrical cells and therefore make use of microtubules for the long-ranged transport of vesicles, mitochondria and RNA, especially along the axons. This challenging task is accomplished via a fine tuning of the microtubule architecture and dynamics. A slight alteration of this complex system can induce neuron diseases, as exemplified with the two proteins investigated in our laboratory, Tau, a microtubule-associated protein which forms cytoplasmic inclusions in neurons of patient suffering of Alzheimer’s disease and, spastin, which mutations induce spastic paraplegia.
ii) Spatio/temporal regulation of mRNA processing
RNA processing in neurons emerges as a critical issue in neurodegeneration as exemplified with proteins like TDP-43, FUS and SMN which are RNA-binding proteins involved in amyotrophic lateral sclerosis (ALS), some types of frontotemporal lobar degeneration (FTLD) and spinal muscular atrophy (SMA), respectively. Interestingly, TDP-43, Fus and SMN are mostly nuclear RNA-binding proteins involved in RNA-splicing which shuttle in the cytoplasm and can associate with stress granules under stress conditions. These observations have boosted the investigations to probe the formation of stress granules in neurons and their putative relation with protein aggregation (TDP-43 and FUS can form cytoplasmic inclusions during neurodegeneration). The role of deregulated RNA splicing remains also to be clarified since proteins like FUS and TDP-43 can be trapped in cytoplasmic stress granules.