Altered expression of glycobiology-related genes in Parkinson's disease brain

Abstract

The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson's disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been limited studies of expression of glycobiology-related genes in PD brain. The current study was performed as an initial attempt to gain new information regarding potential changes in glycoprotein and glycolipid-related genes in PD by investigating the gene expression status for select glycosyltransferases, sialyltransferases, sialidases, sphingosine kinases, and lysosomal enzymes in the substantia nigra and putamen from patients with PD and neurologically normal controls. Results showed altered expression of glycosyltransferase genes (B3GALT2 and B4GALT1) potentially involved in microglial activation and neuroinflammation, sphingosine-1-phosphate (S1P) modulators (SPHK1, SPHK2, and SGPL1) involved in sphingolipid synthesis and metabolism, polysialyltransferase genes (ST8SIA2 and ST8SIA4) that encode enzymes responsible for polysialic acid (polySia) biosynthesis, and the sialidase NEU4, expression of which has been linked to the clearance of storage materials from lysosomes. The data presented here underscore the complexity of the glycolipid/sphingolipid dysregulation in the PD brain and continued and expanded study of these processes may not only provide a greater understanding of the complex roles of aberrant glycosylation sialylation, and sphingolipid synthesis/metabolism in the pathophysiology of PD but may identify potential druggable targets for PD therapeutics.

Keywords: Parkinson’s disease; gene expression; glycolipid; putamen; sphingolipid; substantia nigra.

FIGURE 1

Gene expression changes in substantia nigra from patients with Parkinson’s disease (N = 15) relative to normal, age-matched controls (N = 12). Data are presented as fold change relative to control. Gene expression for glycosyltransferases B3GALT2 and B4GALT1 was significantly higher in patients with PD than in normal controls, while polysialyltransferase genes ST8SIA2 and ST8SIA4 were significantly down-regulated in the PD substantia nigra along with the gene for sialidase NEU4. Genes involved with sphingodine-1-phosphate (S1P) metabolism were significantly dysregulated in PD substantia nigra with expression of sphingosine kinases necessary for S1P synthesis, SPHK1 and SPHK2, significantly down-regulated and gene expression for S1P lyase, SGPL1, involved in the degradation of S1P, was significantly up-regulated. Gene expression for glucosidase beta acid 1 (GBA) was also significantly up-regulated in the PD substantia nigra. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. control.

FIGURE 2

Gene expression changes in putamen from patients with Parkinson’s disease (N = 18) relative to normal, age-matched controls (N = 13). Data are presented as fold change relative to control. In contrast to the numerous changes in gene expression observed in the PD substantia nigra, expression of only one of the genes examined, the lysosomal hydrolytic enzyme β-Galactosidase (GLB1), was significantly altered in the PD putamen. *P < 0.05 vs. control.