Parkinson's disease, Gaucher disease, and bistability in the lysosomal degradation pathway

Sphingolipids are intrinsic components of cell membranes that are transported to lysosomes for degradation into ceramide, which is used in the Golgi to synthesize new sphingolipids. Although sphingolipid metabolism is very complicated, the degradation pathway is relatively simple and converts the sphingolipids to ceramide and sphingosine. Polymorphisms in the genes for enzymes in this pathway are associated with various lysosomal storage disorders, and one of the enzymes, glucosylceramidase (GCase1), is associated with Parkinson's disease and Lewy-body dementia as well as Gaucher disease. We construct a mathematical model of the sphingolipid degradation pathway and show that over a wide range of V_max values of GCase1, the pathway exhibits bi-stability, two steady states with hysteresis between them. In addition, it is known that the formation of synuclein fibrils from monomers and oligomers is influenced by the degradation pathway and, in turn, inhibits GCase1. We show that there are two steady states, one with low fibril production and one with high fibril production, with hysteresis. The fact that there are two steady states with hysteresis presents both challenges and opportunities for drug discovery and dosing. Our work has implications for aging, since it is known that the expression level of the gene for GCase1 declines with age.