TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency
Article first published online: 21 JAN 2014
© 2013 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Annals of Neurology
Volume 74, Issue 6, pages 837–847, December 2013
How to Cite
Flinn, L. J., Keatinge, M., Bretaud, S., Mortiboys, H., Matsui, H., De Felice, E., Woodroof, H. I., Brown, L., McTighe, A., Soellner, R., Allen, C. E., Heath, P. R., Milo, M., Muqit, M. M. K., Reichert, A. S., Köster, R. W., Ingham, P. W. and Bandmann, O. (2013), TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency. Ann Neurol., 74: 837–847. doi: 10.1002/ana.23999
- Issue published online: 21 JAN 2014
- Article first published online: 21 JAN 2014
- Accepted manuscript online: 12 AUG 2013 06:21AM EST
- Manuscript Accepted: 3 AUG 2013
- Manuscript Revised: 30 JUL 2013
- Manuscript Received: 29 NOV 2012
- Parkinson's UK. Grant Numbers: G-0608, G-0901
- BBSRC/Lilly. Grant Number: PhD CASE studentship, BB/I532553/1
- Sheffield Hospitals Charitable Trust. Grant Number: 7884
- Medical Research Council (MRC)
- Cluster of Excellence Frankfurt Macromolecular Complexes at the Goethe University Frankfurt DFG project EXC 115
- DFG. Grant Number: RE1575-1/1
- Humboldt Association
- Wellcome Intermediate Clinical Fellowship. Grant Number: 083601/Z/07/Z
- Parkinson's UK
- the Michael J. Fox Foundation for Parkinson's Research
- Wellcome/MRC PD consortium grant to the University College London Institute of Neurology, University of Sheffield
- MRC Protein Phosphorylation and Ubiquitylation Unit of the University of Dundee
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.
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 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.
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