TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency

Abstract

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

Identification of TP53-induced glycolysis and apoptosis regulator (TIGAR) as the phosphoglycolate-independent 2,3-bisphosphoglycerate phosphatase

“…TIGAR-knockout mice show evidence of increased oxidative stress in the myocardium leading to increased mitophagy [7,34,43]. Furthermore, loss of TIGAR reduces regeneration and tumour formation in the intestinal epithelium, and seems to play a role in a zebrafish model of Parkinson's disease [4,43,44].…”

Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1−/− zebrafish

“…Their genome is fully characterized and contains orthologues for approximately 70% of all human genes, but 82% for all human disease genes (Howe et al ., ). We recently reported our findings in a zebrafish mutant line carrying a Stop mutation ( pink1 Y431 *, from here on referred to as pink1 − / − for homozygous pink1 mutant larvae) in the kinase domain of pink1 , the zebrafish orthologue of the human PD gene PINK1 (Flinn et al ., ). pink1 −/− already resulted in impaired function of the mitochondrial respiratory chain and loss of dopaminergic neurons at 3 days post fertilization (dpf).…”

Live imaging of mitochondrial dynamics in CNS dopaminergic neurons in vivo demonstrates early reversal of mitochondrial transport following MPP+ exposure

“…Zebrafish models have been exploited previously to study the pathogenesis of Parkinson’s disease, and several lines of evidence suggest that zebrafish PD models have both construct and face validity. Zebrafish share highly conserved orthologs of human genes involved in PD pathogenesis, including those encoding proteins known to function in regulating mitochondrial dynamics (Bai et al, 2006; Flinn et al, 2009; Flinn et al, 2013; Milanese et al, 2012). The CNS dopaminergic system of zebrafish is complex, and includes a putative anatomical homologue of the mammalian nigrostriatal projection (Rink and Wullimann, 2001).…”