Unravelling the lipid landscape in lysosomal storage disorders and associated Parkinson's disease: insights for drug discovery (360G-Wellcome-309250_Z_24_Z)

Genetic variants in lysosomal sphingolipid (SL) genes cause lysosomal storage disorders (LSDs) and are strongly linked to Parkinson’s disease (PD) risk. In addition to the lysosomal accumulation of the primary SL substrate in LSDs, secondary lipid alterations can affect the composition and functioning of cellular membranes beyond the lysosome. My proposal will use novel LSD fly models and patient brain tissues to address how these lipid alterations trigger cellular pathologies, and whether there are common lipid signatures across LSDs offering broad-spectrum therapeutic targets. Recently, my lab identified FDA-approved drugs that ameliorate pathology in fly models of two PD-linked LSDs, Gaucher disease and Niemann-Pick Type-A/B, targeting autophagy and SL metabolism respectively. Building on this previous work, Aim 1 will characterise age-dependent, tissue-specific lipid and protein signatures across LSDs through untargeted lipidomic and proteomic analyses. Aims 2 and 3 will characterise and genetically manipulate SL and lipid droplet (LD) metabolic pathways, with the view to identifying common therapeutic targets. Aim 4 will screen combinations of drugs and dietary interventions targeting SLs, LDs and associated intracellular trafficking defects. Finally, these will be validated in Aim 5 using patient-derived neurones, with the aim of translating successful therapies into clinical trials in LSDs and PD.