Fig. 3

Lipid metabolism and lysosomal storage disorders associated with Parkinson's disease. Proteins indicated in orange are associated with Parkinson's disease (PD) and/or atypical Parkinsonian syndromes (APS). Proteins indicated in blue are causal for lysosomal storage disorders (LSDs) but are also linked to PD. The primary syndromes linked to the proteins are indicated in red. The lysosomal integral membrane protein 2 (LIMP-2) is involved in the transport of glucocerebosidase (GCase) from the endoplasmic reticulum to the lysosome. Once in the lysosome, GCase catalyzes the breakdown of glucosylceramide (GluCer) to ceramide and glucose. Ceramide is also obtained by acid sphingomyelinase (ASM) which catalyzes the hydrolysis of sphingomyelin to phosphocholine and ceramide, and GALC which hydrolyzes galactolipids, including galactosylceramide. Both α-synuclein (α-syn) and PLA2G6 have also been associated with ceramide levels, though the exact mechanisms are still unknown. Meanwhile, NPC1 has been associated with GluCer levels, even though NPC1 primarily mediates together with NPC2 intracellular cholesterol trafficking. Furthermore, ATP10B is involved in translocating GluCer towards the cytosolic membrane leaflet. Both ceramide and GluCer levels appear to play an important central role in PD pathogenesis. Meanwhile, NAG degrades heparan sulfate glycosaminoglycans by hydrolyzing terminal N-acetyl-D-glucosamine residues. Finally, VPS13C is a glycerolipid transporter between the endoplasmic reticulum and lysosomes