Laura J. Flinn, Marcus Keatinge, Sandrine Bretaud, Heather Mortiboys, Hideaki Matsui, Elena De Felice, Helen I. Woodroof, Lucy Brown, Aimee McTighe, Rosemarie Waltraud Söllner, Claire E. Allen, Paul Roy Heath, Marta Milo, Miratul M. K. Muqit, Andreas Reichert, Reinhard W. Köster, Philip W. Ingham, Oliver Bandmann
- Objective: Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink−/−) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mechanisms leading to mitochondrial dysfunction and loss of dopaminergic neurons in PINK1 deficiency.
Methods: The effect of PINK1 deficiency on the number of dopaminergic neurons, mitochondrial function, and morphology was assessed in both zebrafish embryos and adults. Genome-wide gene expression studies were undertaken to identify novel pathogenic mechanisms. Functional experiments were carried out to further investigate the effect of PINK1 deficiency on early neurodevelopmental mechanisms and microglial activation.
Results: PINK1 deficiency results in loss of dopaminergic neurons as well as early impairment of mitochondrial function and morphology in Danio rerio. Expression of TigarB, the zebrafish orthologue of the human, TP53-induced glycolysis and apoptosis regulator TIGAR, was markedly increased in pink−/− larvae. Antisense-mediated inactivation of TigarB gave rise to complete normalization of mitochondrial function, with resulting rescue of dopaminergic neurons in pink−/− larvae. There was also marked microglial activation in pink−/− larvae, but depletion of microglia failed to rescue the dopaminergic neuron loss, arguing against microglial activation being a key factor in the pathogenesis.
Interpretation: Pink1−/− zebrafish are the first vertebrate model of PINK1 deficiency with loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD. Ann Neurol 2013;74:837–847
MetadatenAuthor: | Laura J. Flinn, Marcus Keatinge, Sandrine Bretaud, Heather MortiboysORCiDGND, Hideaki Matsui, Elena De Felice, Helen I. Woodroof, Lucy Brown, Aimee McTighe, Rosemarie Waltraud Söllner, Claire E. Allen, Paul Roy Heath, Marta Milo, Miratul M. K. Muqit, Andreas ReichertORCiDGND, Reinhard W. Köster, Philip W. Ingham, Oliver Bandmann |
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URN: | urn:nbn:de:hebis:30:3-442692 |
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URL: | http://eprints.whiterose.ac.uk/78864 |
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DOI: | https://doi.org/10.1002/ana.23999 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/24027110 |
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Parent Title (English): | Annals of neurology |
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Publisher: | Wiley-Blackwell |
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Place of publication: | Hoboken, NJ |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2017/06/08 |
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Year of first Publication: | 2013 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/06/08 |
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Volume: | 74 |
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Issue: | 6 |
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Page Number: | 12 |
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First Page: | 837 |
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Last Page: | 847 |
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Note: | This open access article is distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
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HeBIS-PPN: | 427807670 |
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Institutes: | Biowissenschaften / Biowissenschaften |
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| Medizin / Medizin |
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| Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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| 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 3.0 |
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