2. Academic Validation
  3. A novel allosteric GCase modulator prevents Tau accumulation in GBA1WT and GBA1L444P/L444P cellular models

A novel allosteric GCase modulator prevents Tau accumulation in GBA1WT and GBA1L444P/L444P cellular models

  • Sci Rep. 2025 May 21;15(1):17646. doi: 10.1038/s41598-025-02346-8.
Matteo Ciccaldo 1,  Natàlia Pérez-Carmona 2,  Ester Piovesana 1,  Sara Cano-Crespo 2,  Ana Ruano 2,  Aida Delgado 2,  Ilaria Fregno 3,  Beatriz Calvo-Flores Guzmán 4,  Manolo Bellotto 4,  Maurizio Molinari 3 5,  Joanne Taylor 6,  Stéphanie Papin 1,  Ana María García-Collazo 2,  Paolo Paganetti 7 8 9
Affiliations

Affiliations

  • 1 Laboratory for Aging Disorders, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
  • 2 Gain Therapeutics Sucursal en España, Parc Científic de Barcelona, Barcelona, Spain.
  • 3 Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
  • 4 GT Gain Therapeutics SA, Lugano, Switzerland.
  • 5 School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • 6 Gain Therapeutics Inc, Bethesda, USA.
  • 7 Laboratory for Aging Disorders, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland. paolo.paganetti@usi.ch.
  • 8 Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland. paolo.paganetti@usi.ch.
  • 9 Laboratories for Translational Research EOC, Room 102a, via Chiesa 5, Bellinzona, CH-6500, Switzerland. paolo.paganetti@usi.ch.
PMID: 40399377 DOI: 10.1038/s41598-025-02346-8
Abstract

A slow decline in the autophagy-lysosomal pathway is a hallmark of the normal aging brain. Yet, an acceleration of this cellular function may propel neurodegenerative events. In fact, mutations in genes associated with the autophagy-lysosomal pathway can lead to Parkinson's disease. Also, amyloidogenic protein deposition is observed in lysosomal storage disorders, which are caused by genetic mutations representing risk factors for Parkinson's disease. For example, Gaucher's disease GBA1 mutations leading to defects in lysosomal sphingolipid metabolism cause α-synuclein accumulation. We observed that increased lysosomal Tau accumulation is found in human dermal fibroblasts engineered for inducible Tau expression. Inhibition of the GBA1 product GCase augmented Tau-dependent lysosomal stress and Tau accumulation. Here, we show increased Tau seed-induced Tau accumulation in Gaucher's fibroblasts carrying GBA1 mutations when compared to normal fibroblasts. Pharmacological enhancement of GCase reversed this effect, notably, also in normal fibroblasts. This suggests that boosting GCase activity may represent a therapeutic strategy to slow down aging-dependent lysosomal deficits and brain protein deposition.

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