Zebrafish Models of Autosomal Dominant Ataxias

Abstract

Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal disorders due to its conserved vertebrate genetics that easily support genetic edition and their optic transparency that allows observing the intact CNS and its connections. In addition, its small size and external fertilization help to develop high throughput assays of candidate drugs. Here, we discuss the contributions of zebrafish models to the study of dominant ataxias defining phenotypes, genetic function, behavior and possible treatments. In addition, we review the zebrafish models created for X-linked repeat expansion diseases X-fragile/fragile-X tremor ataxia. Most of the models reviewed here presented neuronal damage and locomotor deficits. However, there is a generalized lack of zebrafish adult heterozygous models and there are no knock-in zebrafish models available for these diseases. The models created for dominant ataxias helped to elucidate gene function and mechanisms that cause neuronal damage. In the future, the application of new genetic edition techniques would help to develop more accurate zebrafish models of dominant ataxias.

Genetic Modeling of the Neurodegenerative Disease Spinocerebellar Ataxia Type 1 in Zebrafish

“…This may explain why gain of function approaches to model autosomal dominant ataxias in zebrafish are currently limited. For most of the pathological genes, the endogenous function has been addressed again by morpholino-mediated approaches, which are summarized well in a recently published review article [ 32 ]. With respect to polyglutamine SCA disease models, SCA3 is the only disease for which a zebrafish model currently exists [ 33 ].…”

Structural Analysis and Spatiotemporal Expression of Atxn1 Genes in Zebrafish Embryos and Larvae

“…There is a critical need to identify the pathological processes and to develop new approaches for treatment or prevention. Therefore, the zebrafish Danio rerio has already become an increasingly important model organism for human neurodegenerative diseases such as the autosomal dominant spinocerebellar ataxias SCA2, SCA3, SCA6, SCA8, and SCA18 (for review see [ 4 ]). It could be important to expand the range of zebrafish models also to SCA1, which is largely caused by a proteotoxic gain-of-function mechanism due to an expansion of a polyglutamine stretch in the human ATXN1 protein [ 5 , 17 ].…”

“…The autosomal dominant spinocerebellar ataxias (ADCAs) are a complex group of neurodegenerative diseases characterized by progressive dysfunction of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord [ 1 , 2 ]. ADCAs can be divided into seven different diseases of episodic ataxias (EA) with recurrent episodes of poor coordination and balance (ataxia) and spinocerebellar ataxias (SCAs), of which 43 different causative loci are known at the present time [ 3 , 4 ]. Seven of these different diseases (SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and DRPLA) are caused by CAG repeats in the coding exons of these unrelated genes, leading to polyglutamine expansions (poly-Q) in the translated gene products.…”

“…There is still a lack of adult zebrafish SCA models and a huge gap in the knowledge of ataxin genes and their functions in zebrafish. Therefore, it is important to expand the range of zebrafish models for the study of the different types of dominant ataxias [ 4 ]. One of the frequent dominant ataxias in which a similar zebrafish protein function is expected is spinocerebellar ataxia type 1 (SCA1).…”

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders

“…As vertebrates, zebrafish, and human genomes show a high homology, about 80% of genes associated with diseases in patients are conserved in zebrafish ( Kalueff et al, 2014 ). Notably, many CNS-related disorders have been successfully modeled in the past and some recent reviews have compiled an exhaustive list of zebrafish models of Amyotrophic Lateral Sclerosis (ALS) ( Braems et al, 2021 ), Hereditary Spastic Paraplegia (HSP) ( Naef et al, 2019 ; Quelle-Regaldie et al, 2021a , b ), Epilepsy ( Rosch et al, 2019 ; Gawel et al, 2020 ), Autism Spectrum Disorder (ASD) ( Meshalkina et al, 2018 ; de Abreu et al, 2020 ), Alzheimer’s Disease (AD) ( Saleem and Kannan, 2018 ), Parkinson’s Disease (PD) ( Unal and Emekli-Alturfan, 2019 ; Najib et al, 2020 ), Huntington’s and Prion-related diseases ( Wang et al, 2021 ), Serotonin syndrome (SS) ( Stewart et al, 2013 ), and Glioblastoma ( Reimunde et al, 2021 ). In this context, our group pioneered the generation of several models of CNS genetic disorders, caused by mutations in gabra1 ( Samarut et al, 2018 ), gabrg2 ( Liao et al, 2019 ), depdc5 ( Swaminathan et al, 2018 ), glra1 ( Samarut et al, 2019 ), or gldc ( Riche et al, 2018 ), and these mutants display clinically-relevant phenotypes such as seizures, ataxic motor phenotypes or hypotonia.…”