ArticleAnnals of neurology2013
TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency.
Article in Annals of neurology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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55 citing papers in PubMed, 89 citations in OpenAlex.
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- C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson's Disease.International journal of molecular sciences · 2024Review
- Assessing Drug Administration Techniques in Zebrafish Models of Neurological Disease.International journal of molecular sciences · 2023Review
- Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.Journal of translational medicine · 2023Review
- SAMPL is a high-throughput solution to study unconstrained vertical behavior in small animals.Cell reports · 2023Article
- Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.Disease models & mechanisms · 2023Article
- Fish Models for Exploring Mitochondrial Dysfunction Affecting Neurodegenerative Disorders.International journal of molecular sciences · 2023Review
- Scalable Apparatus to Measure Posture and Locomotion (SAMPL): a high-throughput solution to study unconstrained vertical behavior in small animals.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
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.
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