Affiliations: Department of Neuroscience, Section of Integrative Physiology, Faculty of Medicine, Graduate School of Medicine University of Miyazaki, Miyazaki, Japan | Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan | Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Note:  Correspondence to: Ryosuke Takahashi, Department of Neurology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3770; Fax: +81 75 761 9780; E-mail: [email protected]
Abstract: Teleost fish have recently been employed as a model for human neurodegenerative diseases. We used toxin exposure and genetic engineering to develop models of Parkinson's disease (PD) in the teleost fish, medaka. Among the toxins examined, 1-methyl-4-phenyl-1,2,3,4–tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), proteasome inhibitors, lysosome inhibitors, and tunicamycin all induced important features of PD in medaka. Specifically, these agents induced dopaminergic cell loss and reduced spontaneous movement, and the latter three toxins produced inclusion bodies that were ubiquitously distributed in the medaka brain. Despite the extensive distribution of these inclusion bodies, the middle diencephalic dopaminergic neurons were particularly susceptible to the effect of the toxins, suggesting that this cluster of dopaminergic neurons is analogous to the human substantia nigra. We have also created a variety of different genetic models using the Targeting Induced Local Lesions in Genomes (TILLING) method, and found that neither PTEN-induced putative kinase 1 (PINK1) mutants nor Parkin mutants disclosed significant dopaminergic cell loss. Surprisingly however, PINK1 and Parkin double mutants exhibited selective dopamine cell loss, as well as aggregation and deficit of mitochondrial activity. Another mutant, the ATP13A2 mutant, also expressed a PD phenotype, exhibiting marked cathepsin D reduction and fingerprint-like structures that are generally found in lysosome storage diseases. Taken together, these data indicate that medaka fish can serve as a new animal model for PD. In this review, we summarize our data and discuss the potential for future application of this animal model.
Keywords: Parkinson's disease, medaka fish, dopaminergic neurons, model animal