Rugarli, Elena I - C 14

Advances in understanding the genetic bases of HSP have highlighted the complexity of the disease pathogenesis and failed to reveal a common pathogenic mechanism. This hampers attempts to find a unifying therapeutic approach for seemingly different disease forms. Our study will allow:

1) to identify shared early-onset pathogenic pathways among different forms of HSP;
2) to discover if the mechanism of axonal death is conserved;
3) to instruct drug-repurposing strategies as novel therapeutic approaches.

In the shorter term, we will translate our results to preclinical trails in the mouse. The long-term perspective is to validate any disease biomarker and pathogenic pathway identified in this study in HSP patient-derived cells and body fluids.

To identify HSP-specific signaling, stress, and death pathways in the neuronal population of interest, the CSMNs and their axons, we employ both ex vivo and in vitro approaches. We make use of genetic mouse models for different forms of HSP that exemplify distinct pathogenic pathways (mitochondrial dysfunction in SPG7; cytoskeletal and lipid droplet impairment in SPG4; disturbances of endoplasmic reticulum-associated degradation and Ca²⁺ signaling in SPG18 and SPG62). We will explore transcriptional, proteome and metabolome changes in the motor cortex and the spinal cord during the progression of the disease. In addition, we have established compartmentalized axonal cultures to exquisitely separate axons from the neuronal soma, and identify potential axono-centric mechanisms of degeneration. Finally, we aim to confirm identified pathways and processes in biological material from human HSP patients and test molecular mechanisms in cellular model systems.