RRC ID |
6243
|
著者 |
Flinn L, Mortiboys H, Volkmann K, Köster RW, Ingham PW, Bandmann O.
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タイトル |
Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio).
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ジャーナル |
Brain
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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.
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巻・号 |
132(Pt 6)
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ページ |
1613-23
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公開日 |
2009-6-1
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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
|
引用数 |
105
|
WOS 分野
|
CLINICAL NEUROLOGY
NEUROSCIENCES
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リソース情報 |
ゼブラフィッシュ |
|