RRC ID 6243
Author Flinn L, Mortiboys H, Volkmann K, Köster RW, Ingham PW, Bandmann O.
Title Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio).
Journal Brain
Abstract Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's 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 Parkinson's 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 Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.
Volume 132(Pt 6)
Pages 1613-23
Published 2009-6-1
DOI 10.1093/brain/awp108
PII awp108
PMID 19439422
MeSH Animals Conserved Sequence Disease Models, Animal* Dopamine / metabolism Drug Evaluation, Preclinical / methods Electron Transport Complex I / deficiency* Embryonic Development / physiology Exons / genetics Gene Knockdown Techniques Microscopy, Electron Mitochondria, Muscle / ultrastructure Mitochondrial Diseases / genetics Neurons / pathology Oligonucleotides, Antisense Parkinson Disease / genetics Parkinson Disease / metabolism* Parkinson Disease / pathology RNA Splice Sites / genetics Substantia Nigra / pathology Swimming Ubiquitin-Protein Ligases / deficiency* Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism Zebrafish
IF 11.337
Times Cited 105
Zebrafish ?