Bandmann 2013 Abstract MiP2013

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Bandmann O, Flinn LJ, Keatinge M, Bretaud S, Mortiboys H, Matsui H, De Felice E,, Brown L, McTighe A, Soellner R, Allen CE, Heath PR, Milo M, Reichert AS, Köster RW, Ingham PW (2013) TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency. Mitochondr Physiol Network 18.08.


Oliver Bandmann

MiP2013, Book of Abstracts Open Access

Bandmann O, Flinn LJ, Keatinge M, Bretaud S, Mortiboys H, Matsui H, De Felice E, Brown L, McTighe A, Soellner R, Allen CE, Heath PR, Milo M, Reichert AS, Koester RW, Ingham PW (2013)

Event: MiPNet18.08_MiP2013

Loss of function mutations in PINK1 typically lead to early onset Parkinson’s Disease (EOPD). 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.

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.

PINK1 deficiency results in progressive 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 normalisation 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.

pink1-/- zebrafish are the first vertebrate model of PINK1 deficiency with progressive loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD.

Labels: MiParea: Genetic knockout;overexpression, Developmental biology  Pathology: Neurodegenerative, Parkinson's 

Organism: Zebrafish, Fishes  Tissue;cell: Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase  Regulation: Aerobic glycolysis, ATP production 

MiP2013, S09 

Affiliations and author contributions

1 - MRC Centre for Developmental and Biomedical Genetics (CDBG), Sheffield, UK;

2 - Sheffield Institute for Translational Neuroscience (SITraN), Dept of Neuroscience; University of Sheffield, UK;

3 - Zoological Institute, TU Braunschweig, Germany;

4 - Dept of Morphology, Biochemistry, Physiology and Animal Productions, Section of Morphology, University of Messina, Polo Universitario dell'Annunziata, Italy;

5 - Helmholtz Zentrum, Institute of Developmental Genetics, Munich, Germany;

6 - Buchmann Institute for Molecular Life Sciences, Mitochondrial Biology and

7 - Mitochondriale Biologie, Zentrum für Molekulare Medizin, Goethe Universität, Frankfurt am Main, Germany

Email: [email protected]