Anagrafe della ricerca

Infantile-onset ascending hereditary spastic paralysis (IAHSP) has been correlated to a biallelic mutation of the Alsin Rho guanine nucleotide exchange factor (ALS2) gene, enconding for a 1657 amino acid protein, that can be found ubiquitously in the body tissues including brain and spinal cord. At higher scale level, IAHSP is characterized by a retrograde degeneration of the upper motor neurons of the pyramidal tracts. Previous studies have highlighted that mutations interfere on proper oligomerization of this protein and thus on his physiological pathway. However, only few of the previous studies have employed methodologies coming from computational molecular modelling which has already been proved as a powerful tool to elucidate molecular phenomena related to neurodegenerative pathologies. This research challenges the development of a 3D structural model of the Alsin protein following mainly two interconnected directions. First computational modelling with particular focus on homology modelling approaches will be used. Information coming from the computational work will allow to proceed toward experiments for resolving the Alsin structure by e.g., Electron Microscopy (cryo-EM). The size of the protein makes this experiments very difficult, and obtaining a model of the whole protein might become even an unachievable task. Hence, it is crucial to firstly rationalize what segment of the protein might be relevant to be resolved and or to find all possible information characterizing the structure before the experiment. The PoliTO unit will pursue this last main objective and will prepare the route for experimental resolution of the protein, to be started within six month by the beginning of the project. Once developed the model it will be employed for molecular modelling and virtual screening and most importantly will be released to the whole scientific community thus speeding up the process of drug discovery worldwide.