The hypothesis of this project is that the different types of autosomal recessive complicated hereditary spastic paraplegia (HSP) share the same pathophysiology of changes in the GSK3 signalling pathway. If confirmed, this pathway might allow a common therapeutic approach these genetically distinct subtypes of HSP. Using human neuronal models for SPG11 and SPG15 differentiated from pluripotent stem cells after gene knockout by CRISPR/Cas9, we will investigate to what extent the GSK3 pathway contributes to neurodegeneration in different autosomal recessive HSP types. We will also investigate changes in the GSK3 pathway in other neuronal cell types relevant for the disease (alpha motoneurons, sensory neurons). In addition, we will test whether GSK3 inhibition can normalize neurodegeneration in CRISPR/Cas9-modified neurons and in patient-specific neurons.
These experiments will allow us to specify neuronal cell types that are dependent on the GSK3 signaling pathway. In addition, mechanisms of action of GSK3 inhibition in autosomal recessive HSP will be identified. Finally, the project aims at predicting therapy responses in complicated HSP types.