Recovery of PEX1-gly843Asp peroxisome dysfunction by small-molecule compounds

Rui Zhang, Li Chen, Sarn Jiralerspong, Ann Snowden, Steven Steinberg, Nancy Braverman

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5569-5574
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 23 2010
Externally publishedYes


  • AAA ATPase
  • Chemical screening
  • Misfolded protein
  • Pharmacologic chaperone
  • Zellweger spectrum

ASJC Scopus subject areas

  • General


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