Allosteric modulation of GCase enhances lysosomal activity and reduces ER stress in GCase-related disorders
Additional information
Authors
Fregno I.,
Pérez-Carmona N.,
Rudinskiy M.,
Soldà T.,
Bergmann T. J.,
Ruano A.,
Delgado A.,
Cubero E.,
Bellotto M.,
García-Collazo A. M.,
Molinari M.
Type
Journal Article
Year
2025
Language
English
Abstract
Variants in the GBA1 gene, encoding the lysosomal enzyme glucosylceramidase beta 1 (GCase), are linked to Parkinson’s disease (PD) and Gaucher disease (GD). Heterozygous variants increase PD risk, while homozygous variants lead to GD, a lysosomal storage disorder. Some GBA1 variants impair GCase maturation in the endoplasmic reticulum, blocking lysosomal transport and causing glucosylceramide accumulation, which disrupts lysosomal function. This study explores therapeutic strategies to address these dysfunctions. Using Site-directed Enzyme Enhancement Therapy (SEE-Tx®), two structurally targeted allosteric regulators (STARs), GT-02287 and GT-02329, were developed and tested in GD patient-derived fibroblasts with relevant GCase variants. Treatment with GT-02287 and GT-02329 improved the folding of mutant GCase, protected the GCaseLeu444Pro variant from degradation, and facilitated the delivery of active GCase to lysosomes. This enhanced lysosomal function and reduced cellular stress. These findings validate the STARs’ mechanism of action and highlight their therapeutic potential for GCase-related disorders, including GD, PD, and Dementia with Lewy Bodies.
Keywords
Parkinson’s disease , Gaucher disease , Glucosylceramidase beta 1 (GCase), Lysosomal storage disorders , Structurally targeted allosteric regulators (STARs) , Site-directed enzyme enhancement therapy (SEE-Tx) , Pharmacological chaperones , Protein misfolding , Lysosomal dysfunction, Allosteric modulation
Journal
IJMS
Volume
26
Number ( Month )
9
Pages (or article number)
4392
Diffusion
License
CC BY
Visibility
Public
Status open access
Gold
