PERK inhibition with GSK2606414 in zebrafish evokes developmental defects consistent with Wolcott-Rallison syndrome phenotypes

Abstract

BackgroundPERK (EIF2AK3) is an endoplasmic reticulum stress kinase whose loss of function disturbs human development, leading to skeletal dysplasia and permanent neonatal diabetes, as observed in the Wolcott-Rallison Syndrome (WRS). The lack of effective, less invasive therapies for developmental diseases highlights the need for animal models that replicate complex pathological phenotypes, while allowing scalable drug screening. Zebrafish, with their high fecundity and rapid development, facilitate efficient in vivo drug testing. MethodsWe aimed to assess the potential of zebrafish for studying PERK function and its pharmacological modulation, particularly as a model for developmental diseases like WRS. Bioinformatic analyses assessed the similarity between human and zebrafish PERK. Increasing concentrations of GSK2606414 were used to inhibit PERK. A combination of behavioural and functional assays evaluated the effects of GSK2606414 on zebrafish skeletal, neuromuscular, and cardiac development. Fluorescence microscopy in transgenic zebrafish expressing fluorescent pancreatic markers and a glucose probe assessed the diabetic-like phenotype. ResultsWe found high similarity between human and zebrafish PERK, along with bioactivity of the PERK inhibitor GSK2606414 in zebrafish. PERK inhibition evoked defects in WRS relevant parameters, such as growth and skeletal development, as well as neuromuscular and cardiac deficiencies, whereas parameters not associated with WRS like otolith area and eye/body ratio remained unaffected. Moreover, PERK inhibition decreased pancreatic ! cell mass and disrupted glucose homeostasis, indicating a diabetic phenotype. ConclusionThese findings evidence zebrafishs potential for studying PERK function and its pharmacological modulation in developmental disorders like WRS, aiding research on pathophysiology and experimental treatments.