Objective: The project aims to further understand the role of the ganglioside GM1 in the relationship between GBA1 mutations and higher α-synuclein levels.

Background: Among all the genetic risk factors that are linked to Parkinson’s disease (PD), mutations in the GBA1 gene are the most important, which they can be identified between 7% and 30% (depending the ethnicity) of PD patients. GBA1 gene is located on chromosome 1 and encode for an enzyme called Glucocerebrosidase (GCase). GCase is a membrane-associated lysosomal enzyme that catalyse the hydrolysis of glucosylceramide in glucose and ceramide.

Gangliosides are glycosphingolipid of membrane containing molecules of sialic acid in which ceramide is the primary lipidic component. They are mainly found in the brain where they are 10- to 30-fold more than other organs and GM1, GD1a, GD1b and GT1b account for 90% of them in the brain.

One of GM1’s most important functions is to keep α-synuclein in the correct conformation when it interacts with the synaptic vesicle.

GCase plays a crucial role in the catabolism of GM1 producing ceramides that may make their way into the salvage pathway of ganglioside and be recycled into new gangliosides. Impairments in GCase activity may result in GM1 deficiency raising α-synuclein levels.

Method: This project exploited fibroblast lines carrying mutation in heterozygosis and homozygosis on GBA1 gene and iPSC-derived dopaminergic neurons from PD patients. The levels of GM1, GCase, and α-synuclein were assessed by immunocytochemical assay while GCase and sialidase (enzymes that convert other ganglioside to GM1) activity were measured with a fluorescent substrate. Genes related to the metabolism of GM1 (B3GALT4 and GLB1) were evaluated with qRT-PCR.

Results: When compared to the WT or isogenic control, all the examined model systems exhibited lower levels of GM1 and higher levels of synuclein (this last one exclusively for dopaminergic neurones). In addition, they showed lower sialidase activity than the WT or isogenic control and lower mRNA levels of the B3GALT4 gene, which is linked to the production of GM1.

Conclusion: To sum up, our study highlighted the possibility that GCase mutations might affect GM1 levels not just via the salvage pathway but also through additional pathways linked to its de novo metabolism and formation from other gangliosides.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gcase-and-ganglioside-gm1-interaction-in-parkinsons-disease/