PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Wolcott-Rallison Syndrome (WRS) is the most common cause of permanent neonatal diabetes mellitus among consanguineous families. The diabetes associated with WRS is non-autoimmune, insulin-requiring and associated with skeletal dysplasia and growth retardation. The therapeutic options for WRS patients rely on permanent insulin pumping or on invasive transplants of liver and pancreas. WRS has a well identified genetic cause: loss-of-function mutations in the gene coding for an endoplasmic reticulum kinase named PERK (protein kinase R-like ER kinase). Currently, WRS research is facilitated by cellular and rodent models with PERK ablation. While these models have unique strengths, cellular models incompletely replicate the organ/system-level complexity of WRS, and rodents have limited scalability for efficiently screening potential therapeutics. To address these challenges, we developed a new in vivo model of WRS by pharmacologically inhibiting PERK in zebrafish. This small vertebrate displays high fecundity, rapid development of organ systems and is amenable to highly efficient in vivo drug testing. PERK inhibition in zebrafish produced typical WRS phenotypes such as glucose dysregulation, skeletal defects, and impaired development. PERK inhibition in zebrafish also produced broad-spectrum WRS phenotypes such as impaired neuromuscular function, compromised cardiac function and muscular integrity. These results show that zebrafish holds potential as a versatile model to study WRS mechanisms and contribute to the identification of promising therapeutic options for WRS.

Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or ß-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.

Swimming against ALS: How to model disease in zebrafish for pathophysiological and behavioral studies.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to progressive disability and motor impairment. Existing therapies provide modest improvements in patient survival, raising a need for new treatments for ALS. Zebrafish is a promising model animal for translational and fundamental research in ALS - it is an experimentally tractable vertebrate, with high homology to humans and an ample experimental toolbox. These advantages allow high-throughput study of behavioral and pathophysiological phenotypes. The last decade saw an increased interest in modelling ALS in zebrafish, leading to the current abundance and variety of available methods and models. Additionally, the rise of gene editing techniques and toxin combination studies has created novel opportunities for ALS studies in zebrafish. In this review, we address the relevance of zebrafish as a model animal for ALS studies, the strategies for model induction and key phenotypical evaluation. Furthermore, we discuss established and emerging zebrafish models of ALS, analyzing their validity, including their potential for drug testing, and highlighting research opportunities in this area.