Subproject 6 "Dopaminergic Degeneration and Lysosomal Dysfunction in SPG11/SPG15" will investigate a novel disease mechanism in the HSP subtypes SPG11/SPG15 with a focus on its potential therapeutic manipulation. The subproject will characterize lysosomal enzyme activities and neurodegenerative phenotypes in different neuron types of SPG11/SPG15 patients. In addition, potentially impaired signaling, metabolic and protein accumulation cascades will be investigated and subsequently validated in biosamples. Finally, we will test the potential of activators of lysosomal enzymes to counteract neurodegeneration in SPG11/SPG15.