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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

ABSTRACT

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.
    Full-text · Article · Jul 2014 · Disease Models and Mechanisms
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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.
    Full-text · Article · Apr 2014 · Progress in Neurobiology
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    • "To address these pathophysiological questions we used a larval zebrafish model previously described by our laboratory (Kabashi et al., 2010b) and addressed the consequences of human TDP-43 expression on motoneuron function. Zebrafish larvae expressing mutTARDBP (but not wtTARDBP) or mutations in other motoneuron disease-related genes, including SOD1, ALS2, FUS, GRN, or SMN1, show symptoms reminiscent of these diseases , such as disruption of motoneuron projections resembling die-back and re-innervation of motor axons and consequent motor deficits (for review, see Kabashi et al., 2010a). Zebrafish have thus been useful for advancing our understanding of disease genetics (Lemmens et al., 2007; Boon et al., 2009; Kabashi et al., 2010b, 2011; Ramesh et al., 2010). "
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    ABSTRACT: TAR DNA binding protein (TDP-43, encoded by the TARDBP gene) has recently been shown to be associated with amyotrophic lateral sclerosis (ALS), but the early pathophysiological deficits causing impairment in motor function are unknown. Here we expressed the wild-type human gene (wtTARDBP) or the ALS mutation G348C (mutTARDBP) in zebrafish larvae and characterized their motor (swimming) activity and the structure and function of their neuromuscular junctions (NMJs). Of these groups only mutTARDBP larvae showed impaired swimming and increased motoneuron vulnerability with reduced synaptic fidelity, reduced quantal transmission, and more orphaned presynaptic and postsynaptic structures at the NMJ. Remarkably, all behavioral and cellular features were stabilized by chronic treatment with either of the L-type calcium channel agonists FPL 64176 or Bay K 8644. These results indicate that expression of mutTARDBP results in defective NMJs and that calcium channel agonists could be novel therapeutics for ALS.
    Full-text · Article · Jan 2013 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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