The role of Rac1 in regulating actin cytoskeleton in GBA2-HSP neurons

Hereditary Spastic Paraplegias (HSPs) are a class of inherited neurodegenerative disorders that mainly damage motor neurons and may present various motor symptoms, such as spasticity, along with more peculiar features in complex HSP forms, such as epilepsy and dementia. Mutations in over 70 genes are associated with HSPs; among them, mutations in GBA2 gene result in a rare form of HSP with ataxia. GBA2 catalyzes the hydrolysis of the lipid glucosylceramide (GlcCer), but also contributes to the homeostasis of glucosylated cholesterol (GlcChol). At the cellular level, neurons modelling GBA2-HSP exhibit defects in the actin cytoskeleton that may be associated to impaired activation of Ras-related C3 botulinum toxin substrate 1 (Rac1), a highly conserved Rho GTPase whose activity is related to altered axonal development and neuronal morphology. Rac1 is also indirectly involved in the regulation of synapse formation. As such, it has been shown to be an attractive therapeutic target for many diseases. My research project focuses on the role of Rac1 in regulating actin cytoskeleton in GBA2-inhibited cerebellar neurons, and on actin polymerization using imaging techniques. Additionally, during my project we developed a Danio rerio model suitable to examine the impact of GBA2 inhibition on phenotypic behaviour and neuronal structure in an in vivo model.