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Updated: Jun 15, 2026
Monitoring Stub1-Mediated Pexophagy
Published on: May 12, 2023
Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds
Rui Zhang1, Li Chen, Sarn Jiralerspong
1McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
Insights
Zellweger spectrum disorder (ZSD) therapies are lacking. Researchers screened 2,080 compounds and identified three drugs that partially restore peroxisome function in patient cells, suggesting potential chaperone therapy for PEX1-p.Gly843Asp.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Zellweger spectrum disorder (ZSD) is a group of severe genetic diseases characterized by defective peroxisome assembly.
- Current management for ZSD is supportive, with no approved therapies, highlighting an urgent need for effective treatments.
- A subset of ZSD patients exhibits a milder, progressive phenotype, emphasizing the potential benefit of early therapeutic intervention.
Purpose of the Study:
- To identify small molecules capable of restoring peroxisome function in Zellweger spectrum disorder fibroblasts.
- To establish a high-content screening assay for identifying drugs that promote peroxisome recovery.
Main Methods:
- A GFP-peroxisome targeting signal 1 reporter assay was used in fibroblasts with the common PEX1-p.Gly843Asp mutation.
- A high-content screening assay was developed and utilized to evaluate 2,080 small molecules for their ability to restore peroxisome function.
- Drug efficacy was confirmed using independent assays to validate the observed improvements in matrix protein import.
Main Results:
- Four compounds were identified that partially restored matrix protein import into peroxisomes.
- Three of these compounds were validated through independent assays, confirming their therapeutic potential.
- The PEX1-p.Gly843Asp mutation appears to involve a misfolded protein, suggesting susceptibility to chaperone-based therapies.
Conclusions:
- The study identified promising compounds for Zellweger spectrum disorder treatment.
- The findings suggest that PEX1-p.Gly843Asp is a misfolded protein targetable by chaperone therapy.
- This research opens avenues for developing early-stage interventions for ZSD patients.
Abstract:
Zellweger spectrum disorder (ZSD) is a heterogeneous group of diseases with high morbidity and mortality caused by failure to assemble normal peroxisomes. There is no therapy for ZSD, but management is supportive. Nevertheless, one-half of the patients have a phenotype milder than classic Zellweger syndrome and exhibit a progressive disease course. Thus, patients would benefit if therapies became available and were instituted early. Recent reports indicate several interventions that result in partial peroxisome recovery in ZSD fibroblasts. To identify drugs that recover peroxisome functions, we expressed a GFP-peroxisome targeting signal 1 reporter in fibroblasts containing the common disease allele, PEX1-p.Gly843Asp. The GFP reporter remained cytosolic at baseline, and improvement in peroxisome functions was detected by the redistribution of the GFP reporter from the cytosol to the peroxisome. We established a high-content screening assay based on this phenotype assay and evaluated 2,080 small molecules. The cells were cultured in chemical for 2 days and then, were fixed and imaged by epifluorescent microscopy on a high-content imaging platform. We identified four compounds that partially recover matrix protein import, and we confirmed three using independent assays. Our results suggest that PEX1-p.G843D is a misfolded protein amenable to chaperone therapy.
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