Modeling neuromuscular diseases in zebrafish

Abstract

Neuromuscular diseases are a diverse group of conditions that affect the motor system and present some overlapping as well as distinct clinical manifestations. Although individually rare, the combined prevalence of NMDs is similar to Parkinson’s. Over the past decade, new genetic mutations have been discovered through whole exome/genome sequencing, but the pathogenesis of most NMDs remains largely unexplored. Little information on the molecular mechanism governing the progression and development of NMDs accounts for the continual failure of therapies in clinical trials. Different aspects of the diseases are typically investigated using different models from cells to animals. Zebrafish emerges as an excellent model for studying genetics and pathogenesis and for developing therapeutic interventions for most NMDs. In this review, we describe the generation of different zebrafish genetic models mimicking NMDs and how they are used for drug discovery and therapy development.

NMJ Analyser: a novel method to quantify neuromuscular junction morphology in zebrafish

“…In this study, we present a specialized image analysis program for the analysis of zebrafish NMJ morphology. Zebrafish are widely utilized in the study of neurodevelopment and NMDs, and the analysis of NMJ morphology is one of the key indicators for motor function ( Singh and Patten 2022 ). The generation of large amounts of data through genetic screening and high-throughput drug assays poses a significant challenge for the manual analysis of NMJ morphology, as it is a time-consuming task.…”

“…Several studies have capitalized on the advantages of the zebrafish and provided important insights in motor axonal growth ( Myers et al 1986 , Chen et al 2012 , Sainath and Granato 2013 ), neuromuscular junction (NMJ) development ( Jing et al 2010 , Bailey et al 2019 ), synaptogenesis ( Jontes et al 2000 , Hutson and Chien 2002 , Panzer et al 2005 , Son et al 2020 ), muscle development ( Skobo et al 2014 , Dubińska-Magiera 2016 , Chen et al 2017 , Yin et al 2022 ), and in NMJ deficits underlying neuromuscular pathologies ( Patten et al 2017 , Butti et al 2021 , Lescouzères et al 2023 ). In the last few decades, the zebrafish has particularly emerged as a valuable tool in studying the pathogenesis and development of therapeutic interventions for various neuromuscular disorders ( Singh and Patten 2022 ). Disturbances in NMJ morphology is one of the characteristic hallmarks of most neuromuscular diseases (NMDs) ( D’Ydewalle et al 2011 , Martínez-Hernández et al 2013 , Butti et al 2021 ).…”

“…Disturbances in NMJ morphology is one of the characteristic hallmarks of most neuromuscular diseases (NMDs) ( D’Ydewalle et al 2011 , Martínez-Hernández et al 2013 , Butti et al 2021 ). Various fluorescent reporter and transgenic zebrafish lines have been developed to model NMDs, which are used for high-throughput drug screening assays ( Giacomotto et al 2015 , Patten et al 2017 , Singh and Patten 2022 , Lescouzères et al 2023 ). High-throughput studies involve evaluating the impact of thousands of potential drugs or toxic substances on NMJ morphology.…”

Zebrafish—A Suitable Model for Rapid Translation of Effective Therapies for Pediatric Cancers

“…Similarly, another neurodevelopmental disorder, Rett syndrome, was effectively modeled in zebrafish, which had observable behavioral alterations throughout their early infancy, including spontaneous and sensory-evoked motor abnormalities as well as thigmotaxis deficits [54,55]. Zebrafish have also been effectively utilized to model neurodegenerative diseases [56], behavioral disorders [57,58], neuromuscular disorders [59][60][61][62][63], aging-related disorders [64][65][66], hematopoietic disorders [67][68][69][70], renal diseases [71][72][73][74], liver diseases [74][75][76][77], and eye diseases [78][79][80][81], to mention a few. In recent years, zebrafish have also been used to study infectious viral diseases, such as Zika [82] and COVID-19 [83].…”

Advancements in 2D and 3D In Vitro Models for Studying Neuromuscular Diseases

“…The NMJ is a specialized synapse between motor neurons (MNs) and skeletal muscle fibers with a complex signaling network [10,11]. Remarkable progress in understanding NMJ development and NMDs has been made by sacrificing experimental animals including non-mammals such as Drosophila [12], Caenorhabditis elegans [13], and zebrafish [14] as well as mammals such as mice, dogs, and pigs [15]. Specifically, mice are the most widely used animal model for NMDs but may not accurately reflect human NMDs because of anatomical and pathophysiological differences as well as molecular-level differences in the NMJ proteome [16].…”