Modeling neurodegenerative disorders in zebrafish

Highlights

• Zebrafish is a highly relevant model species in neurodegenerative research.

• Zebrafish models can help clarify key pathogenic mechanisms of neurodegeneration.

• Neurodegenerative disorders have evolutionarily conserved mechanisms across taxa.

• Neurodegeneration involves complex genetic and molecular deficits across taxa.

Abstract

Neurodegeneration is a major cause of Alzheimer’s, Parkinson’s, Huntington’s, multiple and amyotrophic lateral sclerosis, pontocerebellar hypoplasia, dementia and other related brain disorders. Their complex pathogenesis commonly includes genetic and neurochemical deficits, misfolded protein toxicity, demyelination, apoptosis and mitochondrial dysfunctions. Albeit differing in specific underlying mechanisms, neurodegenerative disorders typically display evolutionarily conserved mechanisms across taxa. Here, we review the role of zebrafish models in recapitulating major human and rodent neurodegenerative conditions, demonstrating this species as a highly relevant experimental model for research on neurodegenerative diseases, and discussing how these fish models can further clarify the underlying genetic, neurochemical, neuroanatomical and behavioral pathogenic mechanisms.

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.