TigarB Causes Mitochondrial Dysfunction and Neuronal Loss in PINK1 Deficiency

被引：74

作者：

Flinn, Laura J. ^{[1
,2
]}

Keatinge, Marcus ^{[1
,2
]}

Bretaud, Sandrine ^{[1
,2
]}

Mortiboys, Heather ^{[2
]}

Matsui, Hideaki ^{[3
]}

De Felice, Elena ^{[1
,2
,4
]}

Woodroof, Helen I. ^{[5
]}

Brown, Lucy ^{[1
,2
]}

McTighe, Aimee ^{[1
,2
]}

Soellner, Rosemarie ^{[6
]}

Allen, Claire E. ^{[1
]}

Heath, Paul R. ^{[2
]}

Milo, Marta ^{[6
]}

Muqit, Miratul M. K. ^{[5
,7
]}

Reichert, Andreas S. ^{[8
,9
]}

Koester, Reinhard W. ^{[3
,6
]}

Ingham, Philip W. ^{[1
,10
]}

Bandmann, Oliver ^{[1
,2
]}

机构：

[1] Univ Sheffield, MRC, Ctr Dev & Biomed Genet, Sheffield S10 2HQ, S Yorkshire, England

[2] Univ Sheffield, Sheffield Inst Translat Neurosci, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England

[3] Braunschweig Univ Technol, Inst Zool, Braunschweig, Germany

[4] Univ Messina, Dept Morphol Biochem Physiol & Anim Prod, Sect Morphol, Messina, Italy

[5] Univ Dundee, MRC, Prot Phosphorylat & Ubiquitylat Unit, Coll Life Sci, Dundee, Scotland

[6] Helmholtz Ctr, Inst Dev Genet, Munich, Germany

[7] Univ Dundee, Coll Med Dent & Nursing, Dundee, Scotland

[8] Buchmann Inst Mol Life Sci, Dept Mitochondrial Biol, Frankfurt, Germany

[9] Goethe Univ Frankfurt, Ctr Mol Med, Dept Mitochondrial Biol, D-60054 Frankfurt, Germany

[10] Nanyang Technol Univ, Imperial Coll London, Lee Kong Chian Sch Med, Singapore 639798, Singapore

来源：

ANNALS OF NEUROLOGY | 2013年 / 74卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

PARKINSONS-DISEASE; DIFFERENTIAL REGULATION; DOPAMINERGIC SYSTEM; ZEBRAFISH BRAIN; DAMAGE; NEURODEGENERATION; VULNERABILITY; SENSITIVITY; METABOLISM; MUTATIONS;

D O I：

10.1002/ana.23999

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveLoss 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. MethodsThe 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. ResultsPINK1 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. InterpretationPink1(-/-) 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

引用

页码：837 / 847

页数：11

共 44 条

[1] Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice [J].