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PERK inhibition with GSK2606414 in zebrafish evokes developmental defects consistent with Wolcott-Rallison syndrome
Background:
PERK (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.
Methods:
We 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.
Results:
We 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.
Conclusion:
These findings evidence zebrafish's potential for studying PERK function and its pharmacological modulation in developmental disorders like WRS, aiding research on pathophysiology and experimental treatments.
Insights
Zebrafish models PERK-related developmental diseases like Wolcott-Rallison Syndrome (WRS). PERK inhibition in zebrafish recapitulates WRS phenotypes, offering a scalable model for studying disease and testing new therapies.
Area of Science:
- Developmental Biology
- Genetics
- Pharmacology
Background:
- Developmental diseases present diagnostic challenges due to heterogeneity and rarity.
- Wolcott-Rallison Syndrome (WRS) involves skeletal dysplasia and neonatal diabetes from PERK (EIF2AK3) mutations.
- Current therapies for WRS are limited, necessitating advanced animal models for drug screening.
Purpose of the Study:
- To evaluate zebrafish as a model for studying PERK function and its pharmacological modulation.
- To assess zebrafish's utility in modeling developmental diseases like WRS.
- To investigate the potential of zebrafish for scalable drug screening in WRS research.
Main Methods:
- Bioinformatic analysis to compare human and zebrafish PERK.
- Pharmacological inhibition of PERK using GSK2606414 in zebrafish.
- Utilized transgenic zebrafish with fluorescent pancreatic markers and glucose probes.
- Combined behavioral and functional assays to assess phenotypes.
Main Results:
- High sequence similarity observed between human and zebrafish PERK.
- PERK inhibition in zebrafish led to decreased beta cell mass and disrupted glucose homeostasis.
- PERK-inhibited zebrafish exhibited skeletal defects, growth impairment, and neuromuscular/cardiac issues relevant to WRS.
- Model selectively recapitulated WRS-associated phenotypes, sparing non-relevant parameters.
Conclusions:
- Zebrafish effectively models PERK function and its modulation in developmental disorders like WRS.
- This model system shows promise for advancing the understanding of WRS pathophysiology.
- Zebrafish offer a scalable platform for experimental treatment research and drug discovery for WRS.
