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Loss of angiotensin II receptor expression in dopamine neurons in Parkinson's disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation.

Zawada WM, Mrak RE, Biedermann J, Palmer QD, Gentleman SM, Aboud O, Griffin WS - Acta Neuropathol Commun (2015)

Bottom Line: The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression.Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

View Article: PubMed Central - PubMed

ABSTRACT

Background: In rodent models of Parkinson's disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.

Results: AT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.

Conclusions: Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

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Intranuclear expression of Nox4 is associated with intranuclear oxidative damage to nucleic acids. Nox4 expression favors nuclear localization in dopamine (pigmented) neurons in prePD and PD patients as compared to AMC individuals (A-C). Quantification of the percent of dopamine neuron nuclei that are Nox4+ (D). Oxidative stress-induced damage to the nucleic acids is demonstrated by a shift of immunohistofluorescently-detected StressMarq signature of oxidized guanosine (8-OH guanosine) into the nuclei of dopamine neurons (E-G) – quantified in panel H. Scale bar is 20 μm. Arrows point to neurons with intranuclear expression of Nox4 or presence of StressMarq-identified 8-OH guanosine. Asterisks in (D and H) identify significant differences from AMC.
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Fig7: Intranuclear expression of Nox4 is associated with intranuclear oxidative damage to nucleic acids. Nox4 expression favors nuclear localization in dopamine (pigmented) neurons in prePD and PD patients as compared to AMC individuals (A-C). Quantification of the percent of dopamine neuron nuclei that are Nox4+ (D). Oxidative stress-induced damage to the nucleic acids is demonstrated by a shift of immunohistofluorescently-detected StressMarq signature of oxidized guanosine (8-OH guanosine) into the nuclei of dopamine neurons (E-G) – quantified in panel H. Scale bar is 20 μm. Arrows point to neurons with intranuclear expression of Nox4 or presence of StressMarq-identified 8-OH guanosine. Asterisks in (D and H) identify significant differences from AMC.

Mentions: Because of our evidence demonstrating a direct link between AngII stimulation of the AT1 and activation of Nox4-dependent generation of superoxide in neural stem cells [12], together with evidence by others of prominent nuclear localization for Nox4 and Nox4-mediated superoxide generation [31,32], we explored the possibility that analogous interactions between the AT1 and Nox4 might occur within the nuclei of dopamine neurons in substantia nigra of Parkinson patients. Moreover, we found co-existence of AT1 and Nox4 immunoreactivity in DAPI-labelled nuclei of dopamine neurons in nigral tissue from AMC, prePD, and PD patients (Figure 7A-C). Quantification of the percent of such dopamine neuron nuclei that were Nox4 immunoreactive showed that 51% of the AMC nuclei were Nox4 positive, whereas in prePD and in PD the nuclear Nox4 was significantly increased and noted in 89% and in 93% of the nuclei examined, respectively (Figure 7D). Such increases in the nuclear Nox4 expression were accompanied by similar increases in oxidative stress-induced damage to neuronal nucleic acids as demonstrated by elevated immunodetection of StressMarq signature of oxidized guanosine (8-hydroxy guanosine; 8-OH guanosine) in the nuclei of dopamine neurons (Figure 7E-G) with a progressive pattern: 31% for AMC < 68% for prePD < 82% for PD (Figure 7H). Taken together our measures support the idea of nuclei-delimited pathologic changes involving AT1 → Nox4 → superoxide-induced nucleic acid damage, which coincide closely with the pathologic progression in the substantia nigra from AMC → prePD → PD.Figure 7


Loss of angiotensin II receptor expression in dopamine neurons in Parkinson's disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation.

Zawada WM, Mrak RE, Biedermann J, Palmer QD, Gentleman SM, Aboud O, Griffin WS - Acta Neuropathol Commun (2015)

Intranuclear expression of Nox4 is associated with intranuclear oxidative damage to nucleic acids. Nox4 expression favors nuclear localization in dopamine (pigmented) neurons in prePD and PD patients as compared to AMC individuals (A-C). Quantification of the percent of dopamine neuron nuclei that are Nox4+ (D). Oxidative stress-induced damage to the nucleic acids is demonstrated by a shift of immunohistofluorescently-detected StressMarq signature of oxidized guanosine (8-OH guanosine) into the nuclei of dopamine neurons (E-G) – quantified in panel H. Scale bar is 20 μm. Arrows point to neurons with intranuclear expression of Nox4 or presence of StressMarq-identified 8-OH guanosine. Asterisks in (D and H) identify significant differences from AMC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4359535&req=5

Fig7: Intranuclear expression of Nox4 is associated with intranuclear oxidative damage to nucleic acids. Nox4 expression favors nuclear localization in dopamine (pigmented) neurons in prePD and PD patients as compared to AMC individuals (A-C). Quantification of the percent of dopamine neuron nuclei that are Nox4+ (D). Oxidative stress-induced damage to the nucleic acids is demonstrated by a shift of immunohistofluorescently-detected StressMarq signature of oxidized guanosine (8-OH guanosine) into the nuclei of dopamine neurons (E-G) – quantified in panel H. Scale bar is 20 μm. Arrows point to neurons with intranuclear expression of Nox4 or presence of StressMarq-identified 8-OH guanosine. Asterisks in (D and H) identify significant differences from AMC.
Mentions: Because of our evidence demonstrating a direct link between AngII stimulation of the AT1 and activation of Nox4-dependent generation of superoxide in neural stem cells [12], together with evidence by others of prominent nuclear localization for Nox4 and Nox4-mediated superoxide generation [31,32], we explored the possibility that analogous interactions between the AT1 and Nox4 might occur within the nuclei of dopamine neurons in substantia nigra of Parkinson patients. Moreover, we found co-existence of AT1 and Nox4 immunoreactivity in DAPI-labelled nuclei of dopamine neurons in nigral tissue from AMC, prePD, and PD patients (Figure 7A-C). Quantification of the percent of such dopamine neuron nuclei that were Nox4 immunoreactive showed that 51% of the AMC nuclei were Nox4 positive, whereas in prePD and in PD the nuclear Nox4 was significantly increased and noted in 89% and in 93% of the nuclei examined, respectively (Figure 7D). Such increases in the nuclear Nox4 expression were accompanied by similar increases in oxidative stress-induced damage to neuronal nucleic acids as demonstrated by elevated immunodetection of StressMarq signature of oxidized guanosine (8-hydroxy guanosine; 8-OH guanosine) in the nuclei of dopamine neurons (Figure 7E-G) with a progressive pattern: 31% for AMC < 68% for prePD < 82% for PD (Figure 7H). Taken together our measures support the idea of nuclei-delimited pathologic changes involving AT1 → Nox4 → superoxide-induced nucleic acid damage, which coincide closely with the pathologic progression in the substantia nigra from AMC → prePD → PD.Figure 7

Bottom Line: The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression.Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

View Article: PubMed Central - PubMed

ABSTRACT

Background: In rodent models of Parkinson's disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.

Results: AT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.

Conclusions: Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

Show MeSH
Related in: MedlinePlus