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: 11.6). 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 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.
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    • "Thus, it can be easily and continuously exposed to different concentrations of amino acids for long periods, whereas in rats the doses administered are rapidly metabolized (Moreira et al., 1989). Furthermore, this species exhibits genetic and anatomic conservation in relation to both mice and humans and a high degree of genetic homology, which is an additional attractive feature for studying genetic basis of human neurological disorders (Barbazuk et al., 2000; Ganser and Dallman, 2009; Guo, 2004; Kabashi et al., 2010). Finally, recent studies have also examined behavioral phenotypes in zebrafish including, social behavior, locomotor activity (Fontaine et al., 2008; Seibt et al., 2010), exploratory activity (Rosemberg et al., 2011), anxiety (Egan et al., 2009), stress (Champagne et al., 2010; Piato et al., 2011), and learning and memory (Blank et al., 2009; Pather and Gerlai, 2009). "
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    ABSTRACT: Hyperprolinemia is an inherited disorder of proline metabolism and patients affected by this disease may present neurological manifestations, including seizures and cognitive dysfunctions. Moreover, an association between adulthood schizoaffective disorders and moderate hyperprolinemia has been reported. However, the mechanisms underlying these behavioral phenotypes still remain unclear. In the present study, we investigated the effect of proline treatments on behavioral parameters in zebrafish, such as locomotor activity, anxiety, and social interaction. Adult zebrafish (Danio rerio) were exposed to proline (1.5 and 3.0 mM) during 1h or 7 days (short- or long-term treatments, respectively). Short-term proline exposure did not promote significant changes on the behavioral parameters observed. Long-term exposure at 1.5 mM proline significantly increased the number of line crossing (47%), the total distance (29%), and the mean speed (33%) when compared to control group. A significant increase in the time spent in the upper portion of the test tank was also observed after this treatment (91%), which may be interpreted as an indicator of anxiolytic behavior. Proline at 1.5 mM also induced social interaction impairment (78%), when compared to the untreated group after long-term treatment. Moreover, these proline-induced behavioral changes in zebrafish were completely reversed by acute administration of an atypical antipsychotic drug (sulpiride), but not by a typical (haloperidol). These findings demonstrate that proline is able to induce schizophrenia-like symptoms in zebrafish, which reinforce the use of this species as a complementary vertebrate model for studying behavioral phenotypes associated with neurological dysfunctions characteristic of metabolic diseases.
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    • "Finally, zebrafish mutant models of human psychiatric diseases can serve as chemical screening start points. The development of relevant zebrafish behavioral and CNS mutants is still in its infancy but rapidly expanding to include neurodegenerative disorders, autism, schizophrenia, and Huntington's disease (see recent reviews by Best and Alderton, 2008; Kabashi et al., 2010; Mathur and Guo, 2010; Tierney, 2011). Small molecule suppressor/enhancer screens on the relevant mutant backgrounds will be a rapid way to identify molecular pathways that interact with disease genes. "
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    ABSTRACT: The larval zebrafish has emerged asa vertebrate model system amenable to small molecule screens for probing diverse biological pathways. Two large-scale small molecule screens examined the effects of thousands of drugs on larval zebrafish sleep/wake and photomotor response behaviors. Both screens identified hundreds of molecules that altered zebrafish behavior in distinct ways. The behavioral profiles induced by these small molecules enabled the clustering of compounds according to shared phenotypes. This approach identified regulators of sleep/wake behavior and revealed the biological targets for poorly characterized compounds. Behavioral screening for neuroactive small molecules in zebrafish is an attractive complement to in vitro screening efforts, because the complex interactions in the vertebrate brain can only be revealed in vivo.
    Developmental Neurobiology 03/2012; 72(3):373-85. DOI:10.1002/dneu.20910 · 4.19 Impact Factor
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