Dopaminergic cell damage and vulnerability to MPTP in Pink1 knockdown zebrafish

Zebrafish Tyrosine Hydroxylase 2 Gene Encodes Tryptophan Hydroxylase

“…Zebrafish, an established vertebrate model for investigating human diseases, has been increasingly used to study PD (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Although the evolutionary distance between humans and zebrafish is about 350 million years, the TH antibodies have cross-species immunoreactivity in zebrafish and can label the ascending dopaminergic system, which is considered as the counterpart of the human nigro-striatal dopamine system (21,22).…”

“…th2 is expressed in the preoptic region (3b), the anterior part of the paraventricular organ (8b), the intermediate part of the paraventricular organ (9b), and the posterior part of the paraventricular organ (10b) during embryogenesis (17,26). Despite different nomenclature of the neuron clusters, there is striking similarity between the patterns of 5-HT and th2.…”

“…ddc is expressed in the th2-positive areas in adult (27)(28)(29)37), but its expression in embryos is restricted to the caudal tuberculum dopaminergic neuron and hindbrain raphe nucleus (14), where th2 is not expressed. In contrast, vmat2 is expressed in the diencephalon with a similar pattern of both th2 and 5-HT (17,26,30,31). We therefore selected vmat2 as the marker gene to determine co-localization of th2 and 5-HT.…”

Tigarb Causes Mitochondrial Dysfunction and Neuronal Loss in Pink1 Deficiency

“…20,35,36 However, all studies using zebrafish as an animal model for PD have universally observed a loss of dopaminergic neurons in the posterior tuberculum after PD toxin exposure such as treatment with MPP1 and frequently also after MOmediated transient PD gene knockdown. 11,37 The functional relevance of the Y431X mutation was confirmed in kinase activity assays but also by studying the effect of this Y431X mutation on pink1 transcript levels. Importantly, our data also suggest that both mitochondrial dysfunction and changes in mitochondrial morphology are early, specific consequences of PINK1 deficiency that do not progress further with age.…”

“…9 Previous studies using the MO strategy to investigate the effects of PINK1 deficiency in zebrafish have led to conflicting results. [10][11][12] Using the targeting induced local lesions in genomes (TILLING) approach, we have now established a stable line carrying a premature stop mutation in the kinase-encoding domain of pink1 (Y431*), the zebrafish orthologue of human PINK1. We provide confirmation that this mutation leads to inactivation of PINK1 catalytic activity and decreased mRNA stability.…”