Transgenic zebrafish models of neurodegenerative diseases

Abstract

Since the introduction of the zebrafish as a model for the study of vertebrate developmental biology, an extensive array of techniques for its experimental manipulation and analysis has been developed. Recently it has become apparent that these powerful methodologies might be deployed in order to elucidate the pathogenesis of human neurodegenerative diseases and to identify candidate therapeutic approaches. In this article, we consider evidence that the zebrafish central nervous system provides an appropriate setting in which to model human neurological disease and we review techniques and resources available for generating transgenic models. We then examine recent publications showing that appropriate phenotypes can be provoked in the zebrafish through transgenic manipulations analogous to genetic abnormalities known to cause human tauopathies, polyglutamine diseases or motor neuron degenerations. These studies show proof of concept that findings in zebrafish models can be applicable to the pathogenic mechanisms underlying human diseases. Consequently, the prospects for providing novel insights into neurodegenerative diseases by exploiting transgenic zebrafish models and discovery-driven approaches seem favorable.

Modeling human neurodegenerative diseases in transgenic systems

“…Use of the I-Sce1 meganuclease and the Tol2 transposon has greatly increased eYciency of transgenesis and decreased mosaicism (Kawakami et al 2000;Sager et al 2010;Thermes et al 2002). Other techniques include sperm-mediated gene transfer, pseudotyped retroviral infection, retroviral infection of in vitro-cultured sperm, and BAC transgenesis (Gama Sager et al 2010).…”

“…Use of the I-Sce1 meganuclease and the Tol2 transposon has greatly increased eYciency of transgenesis and decreased mosaicism (Kawakami et al 2000;Sager et al 2010;Thermes et al 2002). Other techniques include sperm-mediated gene transfer, pseudotyped retroviral infection, retroviral infection of in vitro-cultured sperm, and BAC transgenesis (Gama Sager et al 2010). The ability to regulate gene expression in a cell type-speciWc and temporally restricted manner has been achieved using Gal4/UAS (Halpern et al 2008) and Tet-inducible systems (Huang et al 2011c;Knopf et al 2010).…”

“…Cre or Flp catalyze recombination between two directly repeated loxP or FRT sequences (triangles), respectively. In the example, a region "B" is deleted which may lead to gene inactivation or cause activation of a downstream gene if region "B" contains sequences that block transcription expression (Asakawa et al 2008;Distel et al 2009;Sager et al 2010). A database of currently available zebraWsh Gal4 lines can be found at http://www.zfin.org.…”

Zebrafish for the Study of the Biological Effects of Nicotine

“…Behavioral assays are actively being developed that facilitate the use of zebrafish to study many of the components associated with addiction. Zebrafish are used to study a wide range of human diseases, including but not limited to cardiovascular disease, leukemia, neurodegenerative disease, and solid tumor cancers (Chico, Milo, & Crossman, 2010;Payne & Look, 2009;Sager, Bai, & Burton, 2010;Taylor & Zon, 2009). Zebrafish are also being utilized to advance the field of nicotine research through investigations into neural nicotinic acetylcholine receptors (nAChRs) and studies of the behavioral effects of nicotine (Table 1).…”

Mitophagy and neurodegeneration

“…33 Additionally, the main neurotransmitter systems involving acetylcholine, dopamine, GABA, glycine, glutamate, noradrenaline, and serotonin are all present. 34 With reference to PD, a disorder in which mitophagy has been implicated, although dopaminergic (DA) neurons are identifiable by 18-20 hpf, 35 they are not present in the zebrafish midbrain; however, the observation of Parkinsonian traits in zebrafish treated with a DA neuron-selective toxin implies the existence of functionally equivalent circuitry.…”