Objective: The objective of this work is to investigate the relationship between ganglioside GM1 levels and α-synuclein aggregation in the context of GBA1 mutations.

Background: The GBA1 gene encodes for the GCase that is a lysosomal enzyme that catalyses the hydrolysis of the glycosphingolipids, glucosylceramide and glucosylsphingosine, respectively in glucose and ceramide, and glucose and sphingosine. Mutations in GBA1 gene are considered as the most important genetic risk factor of Parkinson’s disease (PD). Gangliosides are glycosphingolipids, with the ceremide making up the majority of the lipid portion and containing various sialic acid. It has been demonstrated that the particular binding of tetrameric α-synuclein to GM1 in the cell membrane promotes the α-helical structure of the α-synuclein against the β-sheet structure, which has been linked to its pathological aggregation in PD.

The gangliosides’ catabolism begins with the plasma membrane invagination continuing until the lysosome forms. GCase plays a crucial role in the process by hydrolysing the glucosylceramide in both glucose and ceramide. The latter may make their way into the salvage pathway and be recycled into new gangliosides.

Method: This study exploits the SH-SY5Y cells (human neuroblastoma cell line) and fibroblast carrying mutations on GBA1 gene. Through image analysis after staining using specific antibodies, the levels of GM1, GCase, and α-synuclein were determined. GCase’s fluorescent substrate, 4-MUG (4-Methylumbelliferyl β-D-glucopyranoside), was used to evaluate the enzyme’s activity. Gene related to the catabolism and metabolism of GM1 (B3GALT4 and) were evaluated with qPCR.

Results: As previously demonstrated, cells with GBA1 mutations have higher amounts of α-synuclein than WT cells. There is also a statistically significant decrease in the levels of GM1. Furthermore, preliminary results on the B3GALT4 and GLB1 genes showed no alterations in the former gene and a decreased transcription in the latter when compared to the WT.

Conclusion: This work concludes by demonstrating that α-synuclein aggregates may increase as a result of low levels of GM1 caused by a mutation in the GBA1 gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/interaction-of-gcase-and-ganglioside-gm1-in-the-aggregation-of-%ce%b1-synuclein/