Elevating spastin by inhibiting its degradation: a possible therapeutic approach in Hereditary Spastic Paraplegia (HSP)

Hereditary spastic paraplegias (HSPs) are neurodegenerative disorders characterized by progressive spasticity of the lower extremities, due to degeneration of corticospinal neurons. The common type is due to mutations in spastin, a protein involved in cellular division and in intracellular transport. Several studies show that it is crucial to have the right amount of spastin in cells. Curative therapies and approaches to manage HSP progression are completely lacking. However, recent findings indicate that restore the proper dosage of spastin might be beneficial for spastin-deficient HSP patients. To develop therapeutic approaches is crucial to study in detail the mechanisms regulating spastin protein levels. Thus, thanks to Telethon support, we have identified and characterized a new pathway regulating spastin levels. We observed that the protein HIPK2 controls the protein levels of spastin and demonstrated that it is possible to retore the protein levels of spastin by preventing its degradation by using a drug, which inhibits protein degradation. This study provided useful tools to retore the appropriate dosage of spastin the cells and prompted us to plan an evaluation of the effects of these approaches on HSP models that recapitulate human pathological defects, as well as, a further characterization of the molecular players involved in the regulation of spastin degradation. Preliminary studies will be also conducted on cells derived from patients.