Allosteric modulation of GCase enhances lysosomal activity and reduces ER stress in GCase-related disorders
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Fregno, Ilaria
ORCID
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Pérez-Carmona, Natalia
Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
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Rudinskiy, Mikhail
ORCID
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Biology, Swiss Federal Institute of Technology, Zurich, Switzerland
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Solda, Tatiana
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Bergmann, Timothy J.
ORCID
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Ruano, Ana
Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
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Delgado, Aida
Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
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Cubero, Elena
Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
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Bellotto, Manolo
GT Gain Therapeutics SA, Lugano, Switzerland
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García-Collazo, Ana María
Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
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Molinari, Maurizio
ORCID
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - School of Life Sciences, École Polytechnique Fédérale de Lausanne, Switzerland
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Published in:
- IJMS. - 2025, vol. 26, no. 9, p. 4392
English
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.
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Medicine
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CC BY
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Open access status
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gold
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Persistent URL
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https://n2t.net/ark:/12658/srd1332021
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