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Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function

Author

Listed:
  • Thomas Dal Maso

    (VIB
    Vrije Universiteit Brussel)

  • Chiara Sinisgalli

    (University of Padova)

  • Gianluca Zilio

    (University of Padova)

  • Elisa Franzin

    (University of Padova)

  • Isabella Tessari

    (University of Padova)

  • Els Pardon

    (VIB
    Vrije Universiteit Brussel)

  • Jan Steyaert

    (VIB
    Vrije Universiteit Brussel)

  • Steven Ballet

    (Vrije Universiteit Brussel)

  • Elisa Greggio

    (University of Padova
    University of Padova)

  • Wim Versées

    (VIB
    Vrije Universiteit Brussel)

  • Nicoletta Plotegher

    (University of Padova
    University of Padova)

Abstract

The enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-encoding GBA1 gene cause the lysosomal storage disorder Gaucher disease, while heterozygous and homozygous mutations are the most frequent genetic risk factor for Parkinson’s disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of nanobodies (Nbs) targeting and acting as molecular chaperones for GCase. We identify several Nb families that bind with nanomolar affinity to GCase. Based on biochemical characterization, we group the Nbs in two classes: Nbs that improve the activity of the enzyme and Nbs that increase GCase stability in vitro. A selection of the most promising Nbs is shown to improve GCase function in cell models and positively impact the activity of the N370S mutant GCase. These results lay the foundation for the development of new therapeutic routes.

Suggested Citation

  • Thomas Dal Maso & Chiara Sinisgalli & Gianluca Zilio & Elisa Franzin & Isabella Tessari & Els Pardon & Jan Steyaert & Steven Ballet & Elisa Greggio & Wim Versées & Nicoletta Plotegher, 2025. "Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60134-4
    DOI: 10.1038/s41467-025-60134-4
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