Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo
Both genetic and environmental factors increase risk for Parkinson’s disease. Many of the known genetic factors influence α-synuclein aggregation or degradation, whereas most of the identified environmental factors produce oxidative stress. Studies using in vitro approaches have identified mechanism...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/12/2466 |
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| author | Seok Joon Won Rebecca Fong Nicholas Butler Jennifer Sanchez Yiguan Zhang Candance Wong Olive Tambou Nzoutchoum Annie Huynh June Pan Raymond A. Swanson |
| author_facet | Seok Joon Won Rebecca Fong Nicholas Butler Jennifer Sanchez Yiguan Zhang Candance Wong Olive Tambou Nzoutchoum Annie Huynh June Pan Raymond A. Swanson |
| author_sort | Seok Joon Won |
| collection | DOAJ |
| description | Both genetic and environmental factors increase risk for Parkinson’s disease. Many of the known genetic factors influence α-synuclein aggregation or degradation, whereas most of the identified environmental factors produce oxidative stress. Studies using in vitro approaches have identified mechanisms by which oxidative stress can accelerate the formation of α-synuclein aggregates, but there is a paucity of evidence supporting the importance of these processes over extended time periods in brain. To assess this issue, we evaluated α-synuclein aggregates in brains of three transgenic mouse strains: hSyn mice, which overexpress human α-synuclein in neurons and spontaneously develop α-synuclein aggregates; EAAT3<sup>−/−</sup> mice, which exhibit a neuron-specific impairment in cysteine uptake and resultant neuron-selective chronic oxidative stress; and double-transgenic hSyn/EAAT3<sup>−/−</sup> mice. Aggregate formation was evaluated by quantitative immunohistochemistry for phosphoserine 129 α-synuclein and by an α-synuclein proximity ligation assay. Both methods showed that the double transgenic hSyn/EAAT3<sup>−/−</sup> mice exhibited a significantly higher α-synuclein aggregate density than littermate hSyn mice in each brain region examined. Negligible aggregate formation was observed in the EAAT3<sup>−/−</sup> mouse strain, suggesting a synergistic rather than additive interaction between the two genotypes. A similar pattern of results was observed in assessments of motor function: the pole test and rotarod test. Together, these observations indicate that chronic, low-grade neuronal oxidative stress promotes α-synuclein aggregate formation in vivo. This process may contribute to the mechanism by which environmentally induced oxidative stress contributes to α-synuclein pathology in idiopathic Parkinson’s disease. |
| first_indexed | 2024-03-09T17:22:44Z |
| format | Article |
| id | doaj.art-160761b4c516406cad09163cd87b0cc8 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T17:22:44Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-160761b4c516406cad09163cd87b0cc82023-11-24T12:58:34ZengMDPI AGAntioxidants2076-39212022-12-011112246610.3390/antiox11122466Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In VivoSeok Joon Won0Rebecca Fong1Nicholas Butler2Jennifer Sanchez3Yiguan Zhang4Candance Wong5Olive Tambou Nzoutchoum6Annie Huynh7June Pan8Raymond A. Swanson9Department of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USADepartment of Neurology, University of California at San Francisco, San Francisco, CA 94158, USABoth genetic and environmental factors increase risk for Parkinson’s disease. Many of the known genetic factors influence α-synuclein aggregation or degradation, whereas most of the identified environmental factors produce oxidative stress. Studies using in vitro approaches have identified mechanisms by which oxidative stress can accelerate the formation of α-synuclein aggregates, but there is a paucity of evidence supporting the importance of these processes over extended time periods in brain. To assess this issue, we evaluated α-synuclein aggregates in brains of three transgenic mouse strains: hSyn mice, which overexpress human α-synuclein in neurons and spontaneously develop α-synuclein aggregates; EAAT3<sup>−/−</sup> mice, which exhibit a neuron-specific impairment in cysteine uptake and resultant neuron-selective chronic oxidative stress; and double-transgenic hSyn/EAAT3<sup>−/−</sup> mice. Aggregate formation was evaluated by quantitative immunohistochemistry for phosphoserine 129 α-synuclein and by an α-synuclein proximity ligation assay. Both methods showed that the double transgenic hSyn/EAAT3<sup>−/−</sup> mice exhibited a significantly higher α-synuclein aggregate density than littermate hSyn mice in each brain region examined. Negligible aggregate formation was observed in the EAAT3<sup>−/−</sup> mouse strain, suggesting a synergistic rather than additive interaction between the two genotypes. A similar pattern of results was observed in assessments of motor function: the pole test and rotarod test. Together, these observations indicate that chronic, low-grade neuronal oxidative stress promotes α-synuclein aggregate formation in vivo. This process may contribute to the mechanism by which environmentally induced oxidative stress contributes to α-synuclein pathology in idiopathic Parkinson’s disease.https://www.mdpi.com/2076-3921/11/12/2466Parkinson’s diseasecysteineα-synucleinoxidative stressaggregateproximity ligation assay |
| spellingShingle | Seok Joon Won Rebecca Fong Nicholas Butler Jennifer Sanchez Yiguan Zhang Candance Wong Olive Tambou Nzoutchoum Annie Huynh June Pan Raymond A. Swanson Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo Antioxidants Parkinson’s disease cysteine α-synuclein oxidative stress aggregate proximity ligation assay |
| title | Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo |
| title_full | Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo |
| title_fullStr | Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo |
| title_full_unstemmed | Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo |
| title_short | Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo |
| title_sort | neuronal oxidative stress promotes α synuclein aggregation in vivo |
| topic | Parkinson’s disease cysteine α-synuclein oxidative stress aggregate proximity ligation assay |
| url | https://www.mdpi.com/2076-3921/11/12/2466 |
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