A paper published in the International Journal of Molecular Sciences by the Prof. Molinari Laboratory reports on pharmacologic intervention to promote folding of variants of the lysosomal protein glucosylceramidase beta 1 (GCase) linked to Gaucher disease (GD), Parkinson’s disease (PD), and Dementia with Lewy Bodies.
Bellinzona – May 16 2025 – Lysosomes maintain cell’s and tissues’ homeostasis by degrading misfolded proteins, aged or dysfunctional organelles, toxic macromolecules, and by recycling their components. Mutations in the sequence of lysosomal hydrolases such as the GCase prevent protein folding and delivery within the lysosomes with a functional impairment of organellar function and intracellular accumulation of toxic, undigested material. The work performed by Ilaria Fregno, Mikhail Rudinskiy, Tatiana Soldà and Timothy Bergmann in Molinari’s lab in collaboration with Manolo Bellotto and his crew at GAIN therapeutics in Lugano and Barcelona, led to validate the activity of two structurally targeted allosteric regulators (STARS) of GCase folding developed with the Site-directed Enzyme Enhancement Therapy (SEE-Tx®) platform. Tests in cultured and in GD patient-derived cells expressing the wild type and the disease-causing Asn370Ser and Leu444Pro GCase variants revealed the capacity of both STARS to promote folding and lysosomal transport of the mutant polypeptides, to rescue lysosomal function, thus reducing cellular stress. These results highlight the therapeutic potential of the STARS for GCase-related disorders, including GD, PD, and Dementia with Lewy Bodies. The fluorescent, HaloTag-based reporters of lysosomal trafficking and the deep learning image evaluation tool LysoQuant developed in our lab were instrumental for quantitative assessments of the pharmacologic intervention.
