Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2
Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson's disease (PD), with 10-30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.
Authors
- Kathi Ging (ORCID: https://orcid.org/0000-0001-7765-9821)
- Matthew C. Deen (ORCID: https://orcid.org/0000-0002-7902-152X)
- Johannes C. M. Schlachetzki (ORCID: https://orcid.org/0000-0002-7801-9743)
- Jiang‐An Yin (ORCID: https://orcid.org/0000-0002-2134-8693)
- Pierre‐André Gilormini (ORCID: https://orcid.org/0000-0003-1491-1174)
- Stefano Sellitto (ORCID: https://orcid.org/0000-0003-2579-6271)
- Adriano Aguzzi (ORCID: https://orcid.org/0000-0002-0344-6708)
- Ashutosh Dhingra (ORCID: https://orcid.org/0000-0003-2997-7467)
- Christopher K. Glass (ORCID: https://orcid.org/0000-0003-4344-3592)
- Tetiana Serdiuk (ORCID: https://orcid.org/0000-0002-3706-5911)
- Claudio Pisano (ORCID: https://orcid.org/0000-0001-8624-2980)
- Peter Heutink (ORCID: https://orcid.org/0000-0001-5218-1737)
- Lukas Frick (ORCID: https://orcid.org/0000-0002-2147-5369)
- Chiara Trevisan (ORCID: https://orcid.org/0000-0002-3997-094X)
- David J. Vocadlo (ORCID: https://orcid.org/0000-0001-6897-5558)
- Andrea Armani (ORCID: https://orcid.org/0000-0002-4765-9748)
- Xi Chen (ORCID: https://orcid.org/0000-0002-3160-614X)
- Yanping Zhu (ORCID: https://orcid.org/0000-0003-4524-0350)
- Ana Marques
- Desirée Böck
Institutions
- Simon Fraser University (CA)
- University of Zurich (CH)
- German Center for Neurodegenerative Diseases (DE)
- ETH Zurich (CH)
- University of California San Diego (US)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1038/s41531-024-00819-7
- Citations
- 1
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 0.33
Funders
- National Science Foundation
- Michael J. Fox Foundation for Parkinson's Research
- Amicus Therapeutics
- Fondazione Gelu
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Universität Zürich
- NOMIS Stiftung
- Parkinson Schweiz
- Natural Sciences and Engineering Research Council of Canada