Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i>
Oxidative stress is a contributing factor to Parkinson’s disease (PD). Considering the prevalence of sporadic PD, environmental exposures are postulated to increase reactive oxygen species and either incite or exacerbate neurodegeneration. We previously determined that exposure to the common soil ba...
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MDPI AG
2023-04-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/8/1170 |
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| author | Jennifer L. Thies Karolina Willicott Maici L. Craig Madeline R. Greene Cassandra N. DuGay Guy A. Caldwell Kim A. Caldwell |
| author_facet | Jennifer L. Thies Karolina Willicott Maici L. Craig Madeline R. Greene Cassandra N. DuGay Guy A. Caldwell Kim A. Caldwell |
| author_sort | Jennifer L. Thies |
| collection | DOAJ |
| description | Oxidative stress is a contributing factor to Parkinson’s disease (PD). Considering the prevalence of sporadic PD, environmental exposures are postulated to increase reactive oxygen species and either incite or exacerbate neurodegeneration. We previously determined that exposure to the common soil bacterium, <i>Streptomyces venezuelae</i> (<i>S. ven</i>), enhanced oxidative stress and mitochondrial dysfunction in <i>Caenorhabditis elegans</i>, leading to dopaminergic (DA) neurodegeneration. Here, <i>S. ven</i> metabolite exposure in <i>C. elegans</i> was followed by RNA-Seq analysis. Half of the differentially identified genes (DEGs) were associated with the transcription factor DAF-16 (FOXO), which is a key node in regulating stress response. Our DEGs were enriched for Phase I (CYP) and Phase II (UGT) detoxification genes and non-CYP Phase I enzymes associated with oxidative metabolism, including the downregulated xanthine dehydrogenase gene, <i>xdh</i>-<i>1</i>. The XDH-1 enzyme exhibits reversible interconversion to xanthine oxidase (XO) in response to calcium. <i>S. ven</i> metabolite exposure enhanced XO activity in <i>C. elegans</i>. The chelation of calcium diminishes the conversion of XDH-1 to XO and results in neuroprotection from <i>S. ven</i> exposure, whereas CaCl<sub>2</sub> supplementation enhanced neurodegeneration. These results suggest a defense mechanism that delimits the pool of XDH-1 available for interconversion to XO, and associated ROS production, in response to metabolite exposure. |
| first_indexed | 2024-03-11T05:09:20Z |
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| language | English |
| last_indexed | 2024-03-11T05:09:20Z |
| publishDate | 2023-04-01 |
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| series | Cells |
| spelling | doaj.art-ad146a46375643888bc39e869318c2ab2023-11-17T18:43:30ZengMDPI AGCells2073-44092023-04-01128117010.3390/cells12081170Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i>Jennifer L. Thies0Karolina Willicott1Maici L. Craig2Madeline R. Greene3Cassandra N. DuGay4Guy A. Caldwell5Kim A. Caldwell6Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USADepartment of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USADepartment of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USADepartment of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USADepartment of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USADepartment of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USADepartment of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USAOxidative stress is a contributing factor to Parkinson’s disease (PD). Considering the prevalence of sporadic PD, environmental exposures are postulated to increase reactive oxygen species and either incite or exacerbate neurodegeneration. We previously determined that exposure to the common soil bacterium, <i>Streptomyces venezuelae</i> (<i>S. ven</i>), enhanced oxidative stress and mitochondrial dysfunction in <i>Caenorhabditis elegans</i>, leading to dopaminergic (DA) neurodegeneration. Here, <i>S. ven</i> metabolite exposure in <i>C. elegans</i> was followed by RNA-Seq analysis. Half of the differentially identified genes (DEGs) were associated with the transcription factor DAF-16 (FOXO), which is a key node in regulating stress response. Our DEGs were enriched for Phase I (CYP) and Phase II (UGT) detoxification genes and non-CYP Phase I enzymes associated with oxidative metabolism, including the downregulated xanthine dehydrogenase gene, <i>xdh</i>-<i>1</i>. The XDH-1 enzyme exhibits reversible interconversion to xanthine oxidase (XO) in response to calcium. <i>S. ven</i> metabolite exposure enhanced XO activity in <i>C. elegans</i>. The chelation of calcium diminishes the conversion of XDH-1 to XO and results in neuroprotection from <i>S. ven</i> exposure, whereas CaCl<sub>2</sub> supplementation enhanced neurodegeneration. These results suggest a defense mechanism that delimits the pool of XDH-1 available for interconversion to XO, and associated ROS production, in response to metabolite exposure.https://www.mdpi.com/2073-4409/12/8/1170CYP2UGTC25D7.5XO<i>Streptomyces venezuelae</i>bioactivation |
| spellingShingle | Jennifer L. Thies Karolina Willicott Maici L. Craig Madeline R. Greene Cassandra N. DuGay Guy A. Caldwell Kim A. Caldwell Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i> Cells CYP2 UGT C25D7.5 XO <i>Streptomyces venezuelae</i> bioactivation |
| title | Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i> |
| title_full | Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i> |
| title_fullStr | Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i> |
| title_full_unstemmed | Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i> |
| title_short | Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in <i>C. elegans</i> |
| title_sort | xanthine dehydrogenase is a modulator of dopaminergic neurodegeneration in response to bacterial metabolite exposure in i c elegans i |
| topic | CYP2 UGT C25D7.5 XO <i>Streptomyces venezuelae</i> bioactivation |
| url | https://www.mdpi.com/2073-4409/12/8/1170 |
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