Lipid metabolism in the pathogenesis of hereditary spastic paraplegia: genes, biomarkers, and models for therapy – NEUROLIPID

Hereditary spastic paraplegia (HSP) defines a genetically heterogeneous group of disorders characterized by weakness and spasticity of the lower limbs, owing to retrograde degeneration of corticospinal axons. Recently, both genetic and functional studies, largely contributed by research from members of this consortium, have revealed a pathogenic link of HSP with lipid metabolism, pointing to defects in cholesterol (SPG5), fatty acid (SPG49), phospholipid (SPG28, SPG39, SPG54), sphingolipid (SPG26, SPG35, SPG46) metabolism, and lipid droplet turnover (SPG3, SPG4, SPG17, SPG20, SPG31). These data open the way to the identification of novel biomarkers for this pathology, and suggest that therapeutic approaches aiming at restoring normal lipid profiles may prove beneficial in HSP. Lipid composition of biological membranes affects several physiological processes of crucial relevance in neurons, such as endo- and exocytosis, trafficking, and dynamics of organelles. Moreover, lipid molecules may act as direct signalling effectors. Our proposal brings together four groups with complementary expertise with the object to: 1) Establish frequency, natural history, and genotype/phenotype correlations of HSP forms linked to lipid metabolism; 2) Perform lipidomic studies on cell lines and tissues derived from HSP patients and animal models to identify novel biomarkers; 3) Assess cellular consequences of changes in lipid composition and lipid droplets in these forms of HSP; 4) Develop mouse and Drosophila models for a subset of these genes to be used for future preclinical trials.