In the swim of things: Recent insights to neurogenetic disorders from zebrafish

Center for Excellence in Neuromics, Centre Hospitalier de l'Université de Montréal (CHUM) Research Center and Department of Medicine, Université de Montréal, Montréal, QC, Canada.
Trends in Genetics (Impact Factor: 9.92). 08/2010; 26(8):373-81. DOI: 10.1016/j.tig.2010.05.004
Source: PubMed


The advantage of zebrafish as a model to study human pathologies lies in the ease of manipulating gene expression in vivo. Here we focus on recent progress in our understanding of motor neuron diseases and neurodevelopmental disorders and discuss how novel technologies will permit further disease models to be developed. Together these advances set the stage for this simple functional model, with particular advantages for transgenesis, multigenic analyses and chemical biology, to become uniquely suited for advancing the functional genomics of neurological and possibly psychiatric diseases - from understanding the genetics and cell biology of degenerative and developmental disorders to the discovery of therapeutics.

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    • "These models can then be used to study the molecular basis of disease and they will certainly provide novel and useful insights into MNDs. The ability to simultaneously target multiple genes and in different combinations in a single embryo, such as using combinations of morpholinos and mRNAs (Kabashi et al., 2011b; Kabashi et al., 2010a) and by improved genome-editing approaches as reported for the CRISPR/Cas system (Jao et al., 2013) and the Gal4/UAS approach (Liu and Leach, 2011a), represents an attractive strategy for the study of epistasis in MNDs, an important aspect for the analysis of complex diseases that is not easily implemented in other models such as mice. Of general interest for MND models, a recent knockdown screen for modifiers of ALS-related genes in zebrafish identified Epha4 as a gene that, when knocked down, could rescue the phenotype caused by expression of mutant SOD1 or TARDBP. "
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    ABSTRACT: Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.
    Disease Models and Mechanisms 07/2014; 7(7):799-809. DOI:10.1242/dmm.015719 · 4.97 Impact Factor
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    • "These genetic manipulation techniques are used to investigate the function of a particular gene in the etiology of developmental and/or neurodegenerative MNDs. For example, it is possible to validate the effect of human mutations in zebrafish with function loss or gain methods, using wild-type (WT) or mutated human gene transcripts and knocking down the zebrafish ortholog using AMO (for details see Kabashi et al., 2010a; see Section 3.3 for comments on the genetic differences between these methodological approaches). However, the potential zebrafish ortholog target gene, if any, must, at least, be checked for sequence similarity, gene expression pattern, and synteny conservation between human and zebrafish. "
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    ABSTRACT: Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.
    Progress in Neurobiology 04/2014; 118. DOI:10.1016/j.pneurobio.2014.03.001 · 9.99 Impact Factor
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    • "Recently, zebrafish have been gaining momentum as an emerging technology for the study of neurodegenerative diseases [26,27]. Zebrafish are ideal for the development of novel strategies to understand ALS pathogenesis and screen potential therapies due to the fact that they develop quickly, have large numbers of offspring, are less expensive than rodent models, and they are easily amenable to genetic manipulation. "
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    ABSTRACT: Background Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. Results We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. Conclusions This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.
    Molecular Neurodegeneration 08/2012; 7(1):44. DOI:10.1186/1750-1326-7-44 · 6.56 Impact Factor
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