Zebrafish Models of Autosomal Recessive Ataxias

Abstract

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

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

“…In addition, zebrafish are genetically tractable and loss of function studies by means of antisense RNA injections called morpholinos have been used in a number of investigations to model SCA diseases in zebrafish. A recent review summarizes the efforts to model autosomal recessive ataxias in zebrafish in detail [ 30 ]. As morpholino approaches can suffer from off-target effects, some of the described phenotypes await confirmation by targeted mutagenesis, for which the advent of the CRISPR/Cas9-technology is well suited.…”

A nop56 Zebrafish Loss-of-Function Model Exhibits a Severe Neurodegenerative Phenotype

“…Zebrafish (Danio rerio) has become an important model for the study of hereditary neurological disorders, as it has orthologs for 76% to 82% of human genes and its general organization of the CNS is highly similar to humans and many CNS regions relevant for human disease studies show molecular and structural homology in zebrafish [ 31 ]. Many zebrafish genetic models have been developed for neurological disorders, including ataxias [ 32 , 33 , 34 , 35 , 36 , 37 ] and ALS [ 38 , 39 , 40 , 41 ].…”

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.…”