A zebrafish model of PINK1 deficiency reveals key pathway dysfunction including HIF signaling

Priyadarshini, M.; Tuimala, Jarno; Chen, Y.C.; Panula, Pertti

doi:10.1016/j.nbd.2013.02.002

Cited by 21 publications

(20 citation statements)

References 49 publications

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“…Loss of PINK1 has been shown to stabilize HIF1A in murine neurons and murine fibroblasts to sustain proliferation (37). Pink1 loss in zebrafish has been shown to activate HIF1A target genes; however, HIF1A protein expression and the effect on aerobic glycolysis were not assessed (38). In murine astrocytes (NMA), Pink1 loss has been shown to increase glucose metabolism through stabilization of HIF1A in murine astrocytes (NMAs; ref.…”

Section: Discussionmentioning

confidence: 99%

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

et al. 2016

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Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila.

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Section: Discussionmentioning

confidence: 99%

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

et al. 2016

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“…The loss of PINK1 in mice is associated with reduced activities of complex I, II, and aconitase, which are highly sensitive to oxidative stress [12]. Our previous study on the zebrafish model of PINK1 dysfunction identified HIF signaling as one of several significant pathways to be affected [13]. This reinforced the hypothesis that oxidative stress and/or hypoxic stress as a consequence of the loss of PINK1 may lead to PD.…”

Section: Introductionmentioning

confidence: 83%

“…The brains were dissected from 7- and 8-dpf-old larvae and stored in 100% methanol until further use. Digoxigenin (DIG)-labeled probes were made for th1, th2, dat , and pink1 as described earlier [13]. The ISH protocol from Thisse et al was used to perform the experiments [25].…”

Section: Methodsmentioning

confidence: 99%

“…The ISH protocol from Thisse et al was used to perform the experiments [25]. Image analysis was conducted as described earlier [16,26,27]. …”

Section: Methodsmentioning

confidence: 99%

“…It is known that glutathione in the reduced form acts as an antioxidant [14]. The drug L-Glutathione Reduced (LGR) has previously been used to rescue some of the defects caused by PINK1 deficiency [13], but no comprehensive studies using this model have been carried out. Increased oxidative stress is the primary mechanism by which environmental toxins have been associated as potential risk factors for PD [15].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress and Regulation of Pink1 in Zebrafish (Danio rerio)

2013

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Oxidative stress-mediated neuronal dysfunction is characteristic of several neurodegenerative disorders, including Parkinson’s disease (PD). The enzyme tyrosine hydroxylase (TH) catalyzes the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine. A lack of dopamine in the striatum is the most characteristic feature of PD, and the cause of the most dominant symptoms. Loss of function mutations in the PTEN-induced putative kinase (PINK1) gene cause autosomal recessive PD. This study explored the basic mechanisms underlying the involvement of pink1 in oxidative stress-mediated PD pathology using zebrafish as a tool. We generated a transgenic line, Tg(pink1:EGFP), and used it to study the effect of oxidative stress (exposure to H2O2) on pink1 expression. GFP expression was enhanced throughout the brain of zebrafish larvae subjected to oxidative stress. In addition to a widespread increase in pink1 mRNA expression, mild oxidative stress induced a clear decline in tyrosine hydroxylase 2 (th2), but not tyrosine hydroxylase 1 (th1) expression, in the brain of wild-type larvae. The drug L-Glutathione Reduced (LGR) has been associated with anti-oxidative and possible neuroprotective properties. Administration of LGR normalized the increased fluorescence intensity indicating pink1 transgene expression and endogenous pink1 mRNA expression in larvae subjected to oxidative stress by H2O2. In the pink1 morpholino oliogonucleotide-injected larvae, the reduction in the expression of th1 and th2 was partially rescued by LGR. The pink1 gene is a sensitive marker of oxidative stress in zebrafish, and LGR effectively normalizes the consequences of mild oxidative stress, suggesting that the neuroprotective effects of pink1 and LGR may be significant and useful in drug development.

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Genetic Models of Parkinson’s Disease

Kachidian

Gubellini

2020

Clinical Trials in Parkinson's Disease

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A zebrafish model of PINK1 deficiency reveals key pathway dysfunction including HIF signaling

Cited by 21 publications

References 49 publications

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

Oxidative Stress and Regulation of Pink1 in Zebrafish (Danio rerio)

Genetic Models of Parkinson’s Disease

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