Review articleModeling neurodegenerative disorders in zebrafish
Introduction
Neurodegeneration is the main cause of several widespread and debilitating disorders, including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s diseases (HD), as well as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), dementia and other related brain disorders (Agrawal and Biswas, 2015, Chi et al., 2018, Muddapu et al., 2020, Zhou et al., 2022). Their most common clinical symptoms are progressive cognitive and motor deficits (Katsuno et al., 2018) caused by excessive accumulation and aggregation of disease-specific misfolded proteins (Skovronsky et al., 2006), excessive oxidation (induced by free radicals or mitochondrial dysfunction), neuroinflammation and demyelination (Jellinger, 2010). However, the underlying mechanisms of neurodegenerative disorders are complex and remain poorly understood, necessitating further mechanistic studies and the use of animal (experimental) models (McArthur and Borsini, 2008, McGonigle, 2014).
While rodents are presently the most commonly used species for modeling neurodegenerative disorders (Emborg, 2017, Verdier et al., 2015), the zebrafish (Danio rerio) emerges as an important animal model that can be also used to probe molecular and physiological mechanisms of neurodegeneration. These fish are characterized by easily trackable behavioral patterns, shared central nervous system (CNS) and endocrine physiology, fully sequenced genome, high genetic homology with mammals, rapid neurodevelopment, and high potential for pharmacological (De Abreu et al., 2020, Goldsmith, 2004) and genetic manipulations (Choi et al., 2021, Kalueff et al., 2014, Norton and Bally-Cuif, 2010).
Furthermore, zebrafish present some additional practical and methodological advantages (compared to rodent or other vertebrate and invertebrate (e.g., Caenorhabditis elegans) models), including their easier maintenance vs. mammals (Detrich Iii et al., 1998), external fertilization, rapid development, ease of the observation and experimental manipulation of the embryos, as well as the optical clarity of the embryos and even some adult fish strains, hence enabling visualization of individual genes (e.g., fluorescently labeled or dyed) throughout the developmental process using non-invasive imaging techniques (Araya et al., 2016, Tang et al., 2020). Zebrafish also possess a similar (to other vertebrates, including humans) neural structural organization and high genetic homology with human genes involved in clinical AD and other neurodegenerative disorders (Ebrahimie et al., 2017, Kumar et al., 2021, Razali et al., 2021) (see Table 1 for details).
Taken together, all these aspects make zebrafish a particularly promising translational model system for studying CNS disorders, including neurodegenerative diseases. Recognizing this rapidly developing field, here we review zebrafish-based neurodegenerative models, and discuss how they may improve our understanding of various pathobiological aspects of neurodegeneration and its role in human brain disorders.
Section snippets
Alzheimer’s disease (AD)
AD is the most common cause of dementia, caused by accumulating senile plaques (SP) that contain extracellular amyloid beta (Aβ) and neurofibrillary tangles (NFT) of intracellular hyperphosphorylated tau-protein (Goedert, 1993, Hardy and Higgins, 1992, Selkoe and Hardy, 2016). AD includes the early-onset (˂65 years) familial (FAD), and the late-onset (>65 years) sporadic (SAD) subtypes. FAD (Qiu et al., 2009) is associated with mutant APP (Aβ precursor protein), PSEN (Presenelin)1 and PSEN2
Discussion
Mounting evidence summarized here suggests zebrafish as a promising model species to study a wide range of human neurodegenerative disorders. Indeed, zebrafish often parallel and recapitulate rodent models of these disorders, hence often offering a more throughput, less time-consuming and cheaper complementary screening system, compared to traditional rodent models. The possibility to model neurodegenerative disorders in a different taxon (fish vs. mammals) is also important, since it enables
Acknowledgements
This study is supported by the Russian Science Foundation grant № 20-65-46006. The authors declare no conflicts of interest. KNZ was supported by Sirius University of Science and Technology, Sochi, Russia (project ID NRB-RND-2116). KAD and AVK were supported by St. Petersburg State University budget funds (Project ID 93020614). The study partially used the facilities and equipment of the Resource Fund of Applied Genetics MIPT (support grant 075-15-2021-684).
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Contributed equally to this study.