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Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain.

Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T, Manning-Boğ AB, Berry MJ, White LR, Ross GW - Mol Neurodegener (2011)

Bottom Line: Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells.In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cell and Molecular Biology Department, John A, Burns School of Medicine, University of Hawaii, Honolulu, HI 96813 USA. fb@hawaii.edu.

ABSTRACT

Background: Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.

Results: To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.

Conclusions: This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.

No MeSH data available.


Related in: MedlinePlus

Possible Role of GPX4 in Prevention of Apoptotic Cell Death and Production of Neuromelanin. In healthy DA neurons, GPX4 functions to reduce oxidized lipids by oxidizing glutathione (GSH) to glutathione disulfide (GSSG) (above). However, a buildup of oxidized dopamine metabolites or a reduction of glutathione may lead to the synthesis of neuromelanin by GPX4, a process that could compete with reduction of oxidized lipids (below). The accumulated oxidized lipids will be metabolized by 12/15-lipoxygenase (12/15-lipoxy) and may eventually induce AIF and promote apoptotic cell death of DA neurons.
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Figure 7: Possible Role of GPX4 in Prevention of Apoptotic Cell Death and Production of Neuromelanin. In healthy DA neurons, GPX4 functions to reduce oxidized lipids by oxidizing glutathione (GSH) to glutathione disulfide (GSSG) (above). However, a buildup of oxidized dopamine metabolites or a reduction of glutathione may lead to the synthesis of neuromelanin by GPX4, a process that could compete with reduction of oxidized lipids (below). The accumulated oxidized lipids will be metabolized by 12/15-lipoxygenase (12/15-lipoxy) and may eventually induce AIF and promote apoptotic cell death of DA neurons.

Mentions: We have developed a model of the possible competing reactions of GPX4 in reduction of lipids and production of neuromelanin, depicted in Figure 7. GPX4 uses glutathione as a substrate to reduce oxidized lipids (above) [15]. However, a build-up of oxidized forms of DA-related compounds such as DA-quinones may drive the synthesis of neuromelanin from these compounds, a process that may compete with reduction of lipids (below) [21-23]. Depletion of glutathione and upregulation of GPX4 peroxidase activity in response to oxidative stress may further drive the production of neuromelanin and inhibit reduction of lipids [5]. Accumulated oxidized lipids are metabolized by 12/15-lipoxygenase, and metabolite products activate AIF to promote apoptotic cell death [16]. Thus under pathological conditions such as extreme levels of oxidation, the important protective properties of GPX4 may be redirected towards neuromelanin production, and this process may contribute to the loss of DA neurons in PD. Overall, our findings indicate an important neuroprotective role for GPX4 in neurons of the nigrostriatal pathway, and also suggest a role in neuromelanin synthesis associated with primate aging.


Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain.

Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T, Manning-Boğ AB, Berry MJ, White LR, Ross GW - Mol Neurodegener (2011)

Possible Role of GPX4 in Prevention of Apoptotic Cell Death and Production of Neuromelanin. In healthy DA neurons, GPX4 functions to reduce oxidized lipids by oxidizing glutathione (GSH) to glutathione disulfide (GSSG) (above). However, a buildup of oxidized dopamine metabolites or a reduction of glutathione may lead to the synthesis of neuromelanin by GPX4, a process that could compete with reduction of oxidized lipids (below). The accumulated oxidized lipids will be metabolized by 12/15-lipoxygenase (12/15-lipoxy) and may eventually induce AIF and promote apoptotic cell death of DA neurons.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037910&req=5

Figure 7: Possible Role of GPX4 in Prevention of Apoptotic Cell Death and Production of Neuromelanin. In healthy DA neurons, GPX4 functions to reduce oxidized lipids by oxidizing glutathione (GSH) to glutathione disulfide (GSSG) (above). However, a buildup of oxidized dopamine metabolites or a reduction of glutathione may lead to the synthesis of neuromelanin by GPX4, a process that could compete with reduction of oxidized lipids (below). The accumulated oxidized lipids will be metabolized by 12/15-lipoxygenase (12/15-lipoxy) and may eventually induce AIF and promote apoptotic cell death of DA neurons.
Mentions: We have developed a model of the possible competing reactions of GPX4 in reduction of lipids and production of neuromelanin, depicted in Figure 7. GPX4 uses glutathione as a substrate to reduce oxidized lipids (above) [15]. However, a build-up of oxidized forms of DA-related compounds such as DA-quinones may drive the synthesis of neuromelanin from these compounds, a process that may compete with reduction of lipids (below) [21-23]. Depletion of glutathione and upregulation of GPX4 peroxidase activity in response to oxidative stress may further drive the production of neuromelanin and inhibit reduction of lipids [5]. Accumulated oxidized lipids are metabolized by 12/15-lipoxygenase, and metabolite products activate AIF to promote apoptotic cell death [16]. Thus under pathological conditions such as extreme levels of oxidation, the important protective properties of GPX4 may be redirected towards neuromelanin production, and this process may contribute to the loss of DA neurons in PD. Overall, our findings indicate an important neuroprotective role for GPX4 in neurons of the nigrostriatal pathway, and also suggest a role in neuromelanin synthesis associated with primate aging.

Bottom Line: Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells.In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cell and Molecular Biology Department, John A, Burns School of Medicine, University of Hawaii, Honolulu, HI 96813 USA. fb@hawaii.edu.

ABSTRACT

Background: Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.

Results: To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.

Conclusions: This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.

No MeSH data available.


Related in: MedlinePlus