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J. R. Leheste, B. H. Hallas, G. Torres; The Zebrafish Eye: A Model for the Early Detection of Neurodegeneration in Parkinson's Disease. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1413.
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Key issues associated with age-related disease of the central nervous system (CNS), such as Parkinson’s Disease (PD), are early detection and concrete diagnosis. As a result, medical intervention is often delayed leading to a more rapid aggravation of symptoms. An accessible in vivo system for the identification of early signs relevant to human neurodegeneration is therefore needed. The larval zebrafish eye is fully developed after 72h post fertilization (hpf) facilitating easy access to the eye and its neural retina. We believe that the larval zebrafish eye constitutes the ideal model system to identify early morphological signs associated with PD that could be also tested via ophthalmoscopy in humans. The purpose of this study is therefore to establish a reliable zebrafish model for PD allowing the detection of early morphological aberrations associated with the disease.
All zebrafish embryos were treated to prevent pigmentation. Chemically induced zebrafish PD models were generated with either, 5mM H2O2 or 40µg/ml 1,2,3,6-tetrahydropyridine (MPTP) for 24h. Transient genetic zebrafish PD models were generated via RNA interference (RNAi) using zebrafish dj1 (park7) and mdm2 small hairpin oligonucleotides in combination. At 72hpf, all embryos were fixed; dopaminergic (DA) neurons targeted with anti-tyrosine hydroxylase (TH) antibody, and visualized. DA neurons in the ventral diencephalon of the zebrafish brain were identified and counted. Embryos with a reduced DA count are now subject for comparative morphological analysis via confocal microscopy
Exposure to H2O2 specifically ablated approximately 80% of DA neurons found in the ventral diencephalon of the zebrafish brain, an area that corresponds with the nigrostriatal pathway in humans. Exposure to MPTP or RNAi reduced the number of DA neurons in the same area by 10-20% which better mimics the early, asymptomatic stages of PD.
We successfully ablated DA neurons in an area of the zebrafish brain that corresponds to the substantia nigra in humans. We thereby recreated the key feature of human PD in zebrafish. Our chemical and genetic zebrafish PD models mimic different stages of PD thereby facilitating the search for morphological markers specific for those stages in the zebrafish retina. Those markers may be useful in the early diagnosis of PD in humans if they can be accessed via standard ophthalmoscopy.
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