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SUBCELLULAR ALTERATIONS AND NEURONAL DYSFUNCTION IN GAUCHER DISEASE: INVESTIGATING THE ROLE OF SPECIFIC GBA1 MUTATIONS
Elisa Franzinand 5 co-authors
University of Padua
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS06-09PM-047
Presentation
Date TBA
Board: PS06-09PM-047
Event Information
Poster Board
PS06-09PM-047
Poster
View posterAbstract
Gaucher disease (GD) is the most common lysosomal storage disorder, characterized by highly variable phenotypic manifestations, ranging from systemic symptoms to varying degrees of neurological involvement. GD is caused by biallelic mutations in the GBA1 gene, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase). Although more than 500 mutations have been reported in the GBA1 gene, most studies have focused on the most common variants N370S and L444P. The subcellular effects of rarer mutations remain poorly characterized, and genotype-phenotype correlations are still largely unknown. In the present work, we characterize how three neuropathic GBA1 mutations (L444P, P415R and D409H) affect the stability of the enzyme and how they alter the subcellular environment by combining an in silico approach and cellular studies. We evaluated the stability of GCase mutants through automated computational tools and the Cellular Thermal Shift Assay, which together suggest L444P as the most unstable among the three variants. Confocal imaging and electron microscopy experiments were performed on fibroblasts from patients carrying the selected mutations, which revealed Golgi fragmentation, endoplasmic reticulum dilation, and alterations in mitochondrial area. To confirm these findings in a model with a uniform genetic background, we further examined organelle morphology in GBA1 knockdown HEK293T cells expressing the mutants. In the same cellular model, we are analyzing how these mutations alter the enzyme’s interaction network using an enzyme-catalyzed proximity labeling technique. Taken together, these results will provide a clearer view of the molecular mechanisms underlying the broad spectrum of neuropathic phenotypes observed in GD.
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