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Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio).
Brain 132, Part 6, 1613-1623 (2009)
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Currently, only symptomatic therapy is available for Parkinsons disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinsons disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinsons disease. The zebrafish Parkin protein is 62 identical to its human counterpart with 78 identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinsons Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinsons disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinsons disease.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Parkinsons disease; mitochondria; live transgenic zebrafish; catecholaminergic neurons; mitochondrial dysfunction; oxidative damage; alpha-synuclein; disease; model; mutations; pink1; mice
ISSN (print) / ISBN 0006-8950
Zeitschrift Brain: A Journal of Neurology
Quellenangaben Band: 132, Heft: 6, Seiten: 1613-1623, Supplement: Part 6
Verlag Oxford University Press
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)