Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds.

[zellweger syndrome]

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 , PEX 1 -p .G ly 843 A sp . 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 PEX 1 -p .G 8 43 D is a misfolded protein amenable to chaperone therapy .