Glycosphingolipid metabolism and its role in ageing and Parkinson's disease

Abstract

It is well established that lysosomal glucocerebrosidase gene (GBA) variants are a risk factor for Parkinson's disease (PD), with increasing evidence suggesting a loss of function mechanism. One question raised by this genetic association is whether variants of genes involved in other aspects of sphingolipid metabolism are also associated with PD. Recent studies in sporadic PD have identified variants in multiple genes linked to diseases of glycosphingolipid (GSL) metabolism to be associated with PD. GSL biosynthesis is a complex pathway involving the coordinated action of multiple enzymes in the Golgi apparatus. GSL catabolism takes place in the lysosome and is dependent on the action of multiple acid hydrolases specific for certain substrates and glycan linkages. The finding that variants in multiple GSL catabolic genes are over-represented in PD in a heterozygous state highlights the importance of GSLs in the healthy brain and how lipid imbalances and lysosomal dysfunction are associated with normal ageing and neurodegenerative diseases. In this article we will explore the link between lysosomal storage disorders and PD, the GSL changes seen in both normal ageing, lysosomal storage disorders (LSDs) and PD and the mechanisms by which these changes can affect neurodegeneration.

Keywords: Ageing; GBA; Gangliosides; Glycosphingolipid (GSL); Lysosomal storage disease (LSD); Parkinson’s disease (PD).

Fig. 1

Simplified scheme of GSL biosynthesis. Major gangliosides expressed in the central nervous system (CNS) in adult mammalian brain are boxed in pink. Biosynthetic enzyme genes are indicated in blue. GSL names are abbreviated according to Svennerholm [123] and recommended by IUPAC [124]

Fig. 2

Metabolism and trafficking of GSLs. Ceramide is synthesised in the ER and transported to the Golgi by vesicular transport where it is converted to GlcCer. Ceramide can also be bound by CERT and transported by non-vesicular pathway to the late Golgi for the synthesis of SM [125]. Also, via a non-vesicular pathway, the transfer protein FAPP2 transports GlcCer from cis to trans golgi and couples it specifically to the synthesis of globosides [126]. GSLs are then carried by vesicular transport to the plasma membrane where they can be remodelled. Upon endocytosis GSLs are degraded into monosaccharides, free fatty acids, and sphingoid bases, which are recycled for sphingolipid synthesis by the salvage pathway (modified after [127]). ASM, acid sphingomyelinase; β-Gal, β-Galactosidase; Cer, ceramide; CERT, ceramide transfer protein; chol, cholesterol; ER, endoplasmic reticulum; FAPP2, phosphatidylinositol-four-phosphate adapter protein 2; GCase, glucocerebrosidase; GlcCer, glucosylceramide; Hex, hexosaminidase; LacCer, lactosylceramide; Neu, neuraminidase; PM, plasma membrane; SM, sphingomyelin; Sph, sphingosine; Sph1P, sphingosine-1-phosphate. The figures were created with BioRender.com