In this review, we consider recent work using zebrafish to validate and study the functional consequences of mutations of human genes implicated in a broad range of degenerative and developmental disorders of the brain and spinal cord. Also we present technical considerations for those wishing to study their own genes of interest by taking advantage of this easily manipulated and clinically relevant model organism. Zebrafish permit mutational analyses of genetic function (gain or loss of function) and the rapid validation of human variants as pathological mutations. In particular, neural degeneration can be characterized at genetic, cellular, functional, and behavioral levels. Zebrafish have been used to knock down or express mutations in zebrafish homologs of human genes and to directly express human genes bearing mutations related to neurodegenerative disorders such as spinal muscular atrophy, ataxia, hereditary spastic paraplegia, amyotrophic lateral sclerosis (ALS), epilepsy, Huntington's disease, Parkinson's disease, fronto-temporal dementia, and Alzheimer's disease. More recently, we have been using zebrafish to validate mutations of synaptic genes discovered by large-scale genomic approaches in developmental disorders such as autism, schizophrenia, and non-syndromic mental retardation. Advances in zebrafish genetics such as multigenic analyses and chemical genetics now offer a unique potential for disease research. Thus, zebrafish hold much promise for advancing the functional genomics of human diseases, the understanding of the genetics and cell biology of degenerative and developmental disorders, and the discovery of therapeutics. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
"Moreover, one obvious caveat for some current tests for neurogenetic deficits in animals is that the major behavioral paradigms used are based on an individual-trial or a single-session outcome, thus could not eliminate the problem of state/context dependent behavioral fluctuations that could easily mask the differences between the wild-type group and the genetically modified group (yes, labor saving and craving for faster outcome usually comes with a price, which in the end slows down the speed of making important discoveries). Therefore, a carefully designed behavioral test battery for genetically-modified animals that centers on a multiple-session training design while also incorporating other core aspects of cognition is critical to the development of models for the functional genomics of neurogenetic disorders (e.g., Cheng et al., 2011, 2014a; Kabashi et al., 2011). Interval timing fits nicely into this framework, not only because of the multiple-session training methodology whose outcome is very stable across different laboratory environments (Maggi et al., 2014a), but also because interval timing per se is at the core of cognitive and emotional processing (e.g., Cheng et al., 2008; Droit-Volet & Meck, 2007; Matthews & Meck, 2014a, b; Meck, 2001; Meck & MacDonald, 2007). "
[Show abstract][Hide abstract] ABSTRACT: Humans and other animals can be shown to process temporal information as if they use an internal stopwatch that can be “run”, “paused”, and “reset” on command and whose speed of “ticking” is adjustable. In addition, interval-timing behavior can be separated into “clock”, “memory”, and “decision” stages of information processing such that one stage can be modified without changing the others. Moreover, interval-timing procedures can be used to diagnose the behavioral abnormalities associated with transgenic, “knock-out”, and “knock-down” mouse models of human diseases. In conjunction with interval-timing tasks, evaluation of spatial memory and emotional regulation provides the necessary information for identifying the most-likely locus of behavioral deficits in genetically modified mice. Consequently, the Timing and Immersive Memory and Emotional Regulation (TIMER) test battery outlined here is recommended as a tool for behavioral phenotyping.
Neuro-phenome: Cutting-edge approaches and technologies in neurobehavioral genetics., Edited by V. Tucci, 01/2015: chapter Interval-timing protocols and their relevancy to the study of temporal cognition and neurobehavioral genetics.; Wiley-Blackwell.
"Interestingly, a number of promoters are available for neural-specific expression and their inclusion in Tol2 constructs can be used to create transgenic lines with cell-specific expression patterns (Kabashi et al., 2011b). Several MNDs have been modelled in zebrafish by the introduction of human transgenes, but stable transgenic models also have their limitations, the three major ones being ectopic expression, toxic overexpression and variability due to the genetic background (see Kabashi et al., 2011b). New and possibly simpler strategies have come from recent genome-editing approaches and many MND models using these new approaches are being developed, although no gain-of-function models have been published to date. "
[Show abstract][Hide abstract] 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.
"translation) 20–50% 5–20% 1, 2 SOD1 ALS1 (#105400) 21q22 AD A Detoxification enzyme 10–20% 1–5% 3–10 TARDBP ALS10 (#612069) 1p36 AD A RNA binding and exon skipping 5–15% 1–2% 4, 5, 11–16 FUS ALS6 (#608030) 16q12 AD, AR A RNA binding, exon skipping and DNA repair 5% <1% 4, 14, 17 ANG ALS9 (#611895) 14q11 AD A Neovascularization 2% 1% NA PFN1 ALS18 (#614808) 17p13 AD A Disruption of cytoskeletal pathways, axon outgrowth 1–2% Ex. NA ALS2 ALS2 (#205100) 2q33 AR J GEF signaling Ex Ex 18 SETX ALS4 (#602433) 9q34 AD J DNA and RNA metabolism Ex Ex NA VAPB ALS8 (#608627) 20q13 AD A Vesicular trafficking Ex Ex 19 DCTN1 ALS (#105400) 2p13 AD A Axonal transport Ex Ex NA MAPT ALS-FTD (#600274) 17q21 AD A Microtubule assembly and stability Ex Ex NA VCP ALS14 (#613954) 9p13 AD A Vesicle transport and fusion, degradation by the proteasome Ex Ex NA OPTN ALS12 (#613435) 10p13 AD, AR A NF-kB/ubiquitin regulation Ex Ex NA UBQLN2 ALS15 (#300857) Xp11 XL A Ubiquitin-like protein family, degradation by the proteasome Ex Ex NA Abbreviations: A, adult; AD, autosomal dominant; AR, autosomal recessive; Ex, exceptional; Freq, frequency; In, inheritance; J, juvenile; NA, not available; XL, X-linked; Ze, Zebrafish bibliographic references: 1 Ciura et al., 2013; 2 Lee et al., 2013; 3 Da Costa et al., 2014; 4 Kabashi et al., 2011b; 5 Laird et al., 2010; "
[Show abstract][Hide abstract] 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