Ricerc@Sapienza

Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease, caused by mutations in the ALS2 gene encoding for the Alsin protein. Alsin is 184kDa protein composed of several independent structured domains implicated in cell signalling, membrane transport events and cytoskeletal reorganization in mammalian neuronal cell. Most of the associated disease mutations of Alsin are localized in its C-terminal region, leading to a loss of function or cellular mislocalization of the entire protein. This region is characterized by a MORN motif followed by a VPS9 domain: in vitro and in vivo studies on VPS9 domain of Alsin, showed that this domain activates Rab5 GTPase owing to its guanine exchange factor (GEF) activity on this small GTPase family. Together with MORN, VPS9 mediates the homo-oligomerization and localization of Alsin in neuron axons. Recently a missense mutation (R1611W) of VPS9 domain has been identified to lead to the development of IAHSP. To date, no structural information is currently available neither on ALS2 gene product nor on any of its domains. We aim at providing a high-resolution structure and a biophysical characterization of the native and mutated VPS9 domain.