TY  - JOUR
A1  - Flinn, Laura J.
A1  - Keatinge, Marcus
A1  - Bretaud, Sandrine
A1  - Mortiboys, Heather
A1  - Matsui, Hideaki
A1  - De Felice, Elena
A1  - Woodroof, Helen I.
A1  - Brown, Lucy
A1  - McTighe, Aimee
A1  - Söllner, Rosemarie Waltraud
A1  - Allen, Claire E.
A1  - Heath, Paul Roy
A1  - Milo, Marta
A1  - Muqit, Miratul M. K.
A1  - Reichert, Andreas
A1  - Köster, Reinhard W.
A1  - Ingham, Philip W.
A1  - Bandmann, Oliver
T1  - TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency
T2  - Annals of neurology
N2  - 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
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44269
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-442692
UR  - http://eprints.whiterose.ac.uk/78864
N1  - 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.
VL  - 74
IS  - 6
SP  - 837
EP  - 847
PB  - Wiley-Blackwell
CY  - Hoboken, NJ
ER  -