Evidence map›Paper›PMID 39438499›Full record

ArticleNPJ Parkinson's disease2024

Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2.

Kathi Ging, Lukas Frick, Johannes Schlachetzki, Andrea Armani, Yanping Zhu, Pierre-André Gilormini, Ashutosh Dhingra, Desirée Böck, Ana Marques, Matthew Deen and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in NPJ Parkinson's disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Kathi GingInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Lukas FrickInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Johannes SchlachetzkiDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Andrea ArmaniInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Yanping ZhuDepartment of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Pierre-André GilorminiDepartment of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Ashutosh DhingraGerman Center for Neurodegenerative Diseases, Tübingen, Germany.
Desirée BöckInstitute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
Ana MarquesInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Matthew DeenDepartment of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Xi ChenDepartment of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Tetiana SerdiukDepartment of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
Chiara TrevisanInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Stefano SellittoInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Claudio PisanoInstitute of Neuropathology, University of Zurich, Zurich, Switzerland.
Christopher K GlassDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Peter HeutinkGerman Center for Neurodegenerative Diseases, Tübingen, Germany.
Jiang-An YinInstitute of Neuropathology, University of Zurich, Zurich, Switzerland. jiang-an.yin@usz.ch.
David J VocadloDepartment of Chemistry, Simon Fraser University, Burnaby, BC, Canada. dvocadlo@sfu.ca.
Adriano AguzziInstitute of Neuropathology, University of Zurich, Zurich, Switzerland. adriano.aguzzi@uzh.ch.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Identifiers

PMID39438499
PMCPMC11496744

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.