Lipid metabolic perturbation is an early-onset phenotype in adultspinmutants: aDrosophilamodel for lysosomal storage disorders

Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases including lysosomal storage disorders (LSD). A detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. In this study, we systematically analyzed lipid perturbations in spinster (spin) mutants, a Drosophila model of neurodegeneration associated with LSD. Our results highlight an imbalance in brain ceramide and sphingosine as a crucial phenotype in the early stages of neurodegeneration. This perturbation in ceramide metabolism precedes the accumulation of endomembranous structures, manifestation of altered behavior and buildup of lipofuscin (the ageing pigment). Manipulating levels of ceramidase , and, consequently further altering these lipids in spin mutants have allowed us to conclude that ceramide/sphingosine homeostasis is the driving force in disease progression and is integral to spin function in the adult nervous system. Furthermore, we have identified 29 novel and direct interaction partners of Spin. We specifically focused on the lipid carrier protein, Lipophorin (Lpp), and demonstrate its localization with Spin in the adult nervous system and in organs specialized for lipid metabolism including fat bodies and oenocytes. Our observations in spin mutants of altered Lpp immunostaining, and of increased levels of lipid metabolites produced by oenocytes, allude to a functional relevance of the Spin-Lpp interaction. Overall, these results detailing the kinetics of ceramide perturbations in the context of lipofuscin accumulation, as well as the proteomics experiment, represent a valuable resource to further unravel the mechanistic link between systemic changes in lipid metabolism and lysosomal storage disorders. Summary Statement Elevations in specific brain lipids and connections to relevant metabolic genes are identified in a fly model for lysosomal storage disorders. This enables a better understanding of disease progression.