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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

GPX4 is found primarily in Neuromelanin-expressing neurons of SN. GPX4 immunoreactivity is present in most cells expressing neuromelanin but is absent in many cells expressing TH but not neuromelanin. A. Example of cells expressing TH but not neuromelanin. Light microscope images (above left) were filtered for neuromelanin (blue, above center) to compare with TH immunoreactivity (magenta, above right) and GPX4 immunoreactivity (green, below left). GPX4 images combined with neuromelanin (below, middle) and TH immunoreactivity (below, right) are also shown for comparison. GPX4 is present in surrounding glia but absent in TH-expressing neurons. B. Examples of TH and neuromelanin expressing neurons. GPX4 is present in most cells with neuromelanin. C. GPX4 immunoreactivity is prominent in neurons containing neuromelanin but no longer expressing TH. (Note: as images were not taken with confocal microscopy, color changes only show only co-localization of area and not intracellular co-localization). Scale bars: 20 μm.
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Figure 2: GPX4 is found primarily in Neuromelanin-expressing neurons of SN. GPX4 immunoreactivity is present in most cells expressing neuromelanin but is absent in many cells expressing TH but not neuromelanin. A. Example of cells expressing TH but not neuromelanin. Light microscope images (above left) were filtered for neuromelanin (blue, above center) to compare with TH immunoreactivity (magenta, above right) and GPX4 immunoreactivity (green, below left). GPX4 images combined with neuromelanin (below, middle) and TH immunoreactivity (below, right) are also shown for comparison. GPX4 is present in surrounding glia but absent in TH-expressing neurons. B. Examples of TH and neuromelanin expressing neurons. GPX4 is present in most cells with neuromelanin. C. GPX4 immunoreactivity is prominent in neurons containing neuromelanin but no longer expressing TH. (Note: as images were not taken with confocal microscopy, color changes only show only co-localization of area and not intracellular co-localization). Scale bars: 20 μm.

Mentions: We used spectral imaging to compare GPX4 immunoreactivity in SN cells with presence or absence of neuromelanin. Figure 2A depicts a group of TH-positive cells that are negative for neuromelanin. GPX4 immunoreactivity is largely absent in these cells, although it can be seen in surrounding glia and white matter. Figure 2B shows a group of TH- and neuromelanin-positive neurons. GPX4 immunoreactivity was visible in most TH-positive cells expressing neuromelanin, although expression levels varied from cell to cell. Figure 2C shows a group of TH-negative, neuromelanin-positive cells. GPX4 labeling was strongest within these cells. These findings suggest GPX4 expression increases in SN neurons with the development of neuromelanin and continues to increase as expression of TH is lost.


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)

GPX4 is found primarily in Neuromelanin-expressing neurons of SN. GPX4 immunoreactivity is present in most cells expressing neuromelanin but is absent in many cells expressing TH but not neuromelanin. A. Example of cells expressing TH but not neuromelanin. Light microscope images (above left) were filtered for neuromelanin (blue, above center) to compare with TH immunoreactivity (magenta, above right) and GPX4 immunoreactivity (green, below left). GPX4 images combined with neuromelanin (below, middle) and TH immunoreactivity (below, right) are also shown for comparison. GPX4 is present in surrounding glia but absent in TH-expressing neurons. B. Examples of TH and neuromelanin expressing neurons. GPX4 is present in most cells with neuromelanin. C. GPX4 immunoreactivity is prominent in neurons containing neuromelanin but no longer expressing TH. (Note: as images were not taken with confocal microscopy, color changes only show only co-localization of area and not intracellular co-localization). Scale bars: 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: GPX4 is found primarily in Neuromelanin-expressing neurons of SN. GPX4 immunoreactivity is present in most cells expressing neuromelanin but is absent in many cells expressing TH but not neuromelanin. A. Example of cells expressing TH but not neuromelanin. Light microscope images (above left) were filtered for neuromelanin (blue, above center) to compare with TH immunoreactivity (magenta, above right) and GPX4 immunoreactivity (green, below left). GPX4 images combined with neuromelanin (below, middle) and TH immunoreactivity (below, right) are also shown for comparison. GPX4 is present in surrounding glia but absent in TH-expressing neurons. B. Examples of TH and neuromelanin expressing neurons. GPX4 is present in most cells with neuromelanin. C. GPX4 immunoreactivity is prominent in neurons containing neuromelanin but no longer expressing TH. (Note: as images were not taken with confocal microscopy, color changes only show only co-localization of area and not intracellular co-localization). Scale bars: 20 μm.
Mentions: We used spectral imaging to compare GPX4 immunoreactivity in SN cells with presence or absence of neuromelanin. Figure 2A depicts a group of TH-positive cells that are negative for neuromelanin. GPX4 immunoreactivity is largely absent in these cells, although it can be seen in surrounding glia and white matter. Figure 2B shows a group of TH- and neuromelanin-positive neurons. GPX4 immunoreactivity was visible in most TH-positive cells expressing neuromelanin, although expression levels varied from cell to cell. Figure 2C shows a group of TH-negative, neuromelanin-positive cells. GPX4 labeling was strongest within these cells. These findings suggest GPX4 expression increases in SN neurons with the development of neuromelanin and continues to increase as expression of TH is lost.

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