Study of the molecular characteristics of spastic paraplegia type 11: its impact on oxidative metabolism and response to drugs treatments

The Hereditary Spastic Paraplegias (HSPs) are inherited neurological disorders characterized by progressive spasticity and pyramidal weakness, predominantly in the lower limbs. Collectively, HSPs are rare conditions affecting any age, and cause important health problems due to gradual functional deterioration, sometimes leading to premature death. Over 80 genes are currently associated with HSPs and the number is still increasing, as well as the clinical features associated with the disease. We focused our study on SPG11-HSP, the most frequent form of autosomal recessive HSP. This is a neurodegenerative disease with no cure requiring new insights on the mechanisms to find new opportunity to therapy. We tested SPG11 patients’ biological material and engineered SPG11 knockout neuroblastoma cell line. SPG11 encodes SPATACSIN, a large protein without a clear specific function associated to the disease. We demonstrated a loss-of-function mechanism with an involvement of mitochondria with consequences on oxidative metabolism. Then, with a multi-omics approach on SPG11 patients’ fibroblasts, we extended the knowledge of the putative pathway involved in SPG11 disease thanks to proteomic analysis and we defined putative disease biomarkers with lipidomic analysis. Lastly, the pharmacological approach with the two FDA approved drugs, ataluren and miglustat highlighted that the former did not appear to impact on SPG11 cells whereas the latter evidenced a slight modulatory effect on the new pathways identified through proteomic in patients’ fibroblasts. Altogether, studies performed during this doctoral work further underlined the usefulness of in vivo and in vitro studies on patients and their biological material as a tool for future investigations to dissect pathogenesis and to hypothesize effective therapies. Nonetheless further studies remain imperative to challenge SPG11-HSP disease progression with the ambition to modify tomorrow clinical practice in the large number of young children with spasticity. This increases the need of a more precise diagnosis at the pre-symptomatic stage, and potentiality to undergo safe and efficacious pharmacological treatments