TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency

Laura J Flinn; Marcus Keatinge; Sandrine Bretaud; Heather Mortiboys; Hideaki Matsui; Elena De Felice; Helen I Woodroof; Lucy Brown; Aimee McTighe; Rosemarie Soellner; Claire E Allen; Paul R Heath; Marta Milo; Miratul M K Muqit; Andreas S Reichert; Reinhard W Köster; Philip W Ingham; Oliver Bandmann

doi:10.1002/ana.23999

TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency

Laura J Flinn, Marcus Keatinge, Sandrine Bretaud, Heather Mortiboys, Hideaki Matsui, Elena De Felice, Helen I Woodroof, Lucy Brown, Aimee McTighe, Rosemarie Soellner, Claire E Allen, Paul R Heath, Marta Milo, Miratul M K Muqit, Andreas S Reichert, Reinhard W Köster, Philip W Ingham, Oliver Bandmann

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	837-47
Number of pages	11
Journal	Annals of Neurology
Volume	74
Issue number	6
Early online date	12 Aug 2013
DOIs	https://doi.org/10.1002/ana.23999
Publication status	Published - 21 Jan 2014

Bibliographical note

Funding

Financial support from Parkinson’s UK (G-0608; G-0901) BBSRC/Lilly (PhD CASE studentship, BB/I532553/1) and Sheffield Hospitals Charitable Trust(7884) for O.B. and from the Medical Research Council (MRC) to P.W.I. is gratefully acknowledged. This work was also supported by the Cluster of Excellence Frankfurt Macromolecular Complexes at the Goethe University Frankfurt DFG project EXC 115, the DFG grant RE1575-1=1 (A.S.R.), and the Humboldt Association(R.W.K.). M.M.K.M. is funded by a Wellcome Intermediate Clinical Fellowship (083601=Z=07=Z); Parkinson’s UK; the Michael J. Fox Foundation for Parkinson’s Research; a Wellcome/MRC PD consortium grant to the University College London Institute of Neurology, Uni-versity of Sheffield, and MRC Protein Phosphorylation and Ubiquitylation Unit of the University of Dundee;and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica, and Pfizer).

Keywords

Animals
Animals, Genetically Modified
Apoptosis Regulatory Proteins/genetics
Disease Models, Animal
Dopaminergic Neurons/metabolism
Larva/genetics
Microglia/metabolism
Mitochondria/metabolism
Mitochondrial Diseases/genetics
Parkinson Disease/genetics
Protein Serine-Threonine Kinases/deficiency
Zebrafish/genetics
Zebrafish Proteins/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., & Bandmann, O. (2014). TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency. Annals of Neurology, 74(6), 837-47. https://doi.org/10.1002/ana.23999

Flinn, LJ, Keatinge, M, Bretaud, S, Mortiboys, H, Matsui, H, De Felice, E, Woodroof, HI, Brown, L, McTighe, A, Soellner, R, Allen, CE, Heath, PR, Milo, M, Muqit, MMK, Reichert, AS, Köster, RW, Ingham, PW & Bandmann, O 2014, 'TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency', Annals of Neurology, vol. 74, no. 6, pp. 837-47. https://doi.org/10.1002/ana.23999

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title = "TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency",

abstract = "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.",

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author = "Flinn, {Laura J} and Marcus Keatinge and Sandrine Bretaud and Heather Mortiboys and Hideaki Matsui and {De Felice}, Elena and Woodroof, {Helen I} and Lucy Brown and Aimee McTighe and Rosemarie Soellner and Allen, {Claire E} and Heath, {Paul R} and Marta Milo and Muqit, {Miratul M K} and Reichert, {Andreas S} and K{\"o}ster, {Reinhard W} and Ingham, {Philip W} and Oliver Bandmann",

note = "{\textcopyright} 2013 American Neurological Association.",

year = "2014",

month = jan,

day = "21",

doi = "10.1002/ana.23999",

language = "English",

volume = "74",

pages = "837--47",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons",

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TY - JOUR

T1 - TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency

AU - Flinn, Laura J

AU - Keatinge, Marcus

AU - Bretaud, Sandrine

AU - Mortiboys, Heather

AU - Matsui, Hideaki

AU - De Felice, Elena

AU - Woodroof, Helen I

AU - Brown, Lucy

AU - McTighe, Aimee

AU - Soellner, Rosemarie

AU - Allen, Claire E

AU - Heath, Paul R

AU - Milo, Marta

AU - Muqit, Miratul M K

AU - Reichert, Andreas S

AU - Köster, Reinhard W

AU - Ingham, Philip W

AU - Bandmann, Oliver

PY - 2014/1/21

Y1 - 2014/1/21

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.

AB - 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.

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KW - Apoptosis Regulatory Proteins/genetics

KW - Disease Models, Animal

KW - Dopaminergic Neurons/metabolism

KW - Larva/genetics

KW - Microglia/metabolism

KW - Mitochondria/metabolism

KW - Mitochondrial Diseases/genetics

KW - Parkinson Disease/genetics

KW - Protein Serine-Threonine Kinases/deficiency

KW - Zebrafish/genetics

KW - Zebrafish Proteins/genetics

U2 - 10.1002/ana.23999

DO - 10.1002/ana.23999

M3 - Article

C2 - 24027110

SN - 0364-5134

VL - 74

SP - 837

EP - 847

JO - Annals of Neurology

JF - Annals of Neurology

IS - 6

ER -

TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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