Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration
The causes of nigrostriatal cell death in idiopathic Parkinson’s disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezue...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412023005020 |
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| author | Anna-Katharina Ückert Sina Rütschlin Simon Gutbier Nathalie Christine Wörz Mahfuzur R. Miah Airton C. Martins Isa Hauer Anna-Katharina Holzer Birthe Meyburg Ann-Kathrin Mix Christof Hauck Michael Aschner Thomas Böttcher Marcel Leist |
| author_facet | Anna-Katharina Ückert Sina Rütschlin Simon Gutbier Nathalie Christine Wörz Mahfuzur R. Miah Airton C. Martins Isa Hauer Anna-Katharina Holzer Birthe Meyburg Ann-Kathrin Mix Christof Hauck Michael Aschner Thomas Böttcher Marcel Leist |
| author_sort | Anna-Katharina Ückert |
| collection | DOAJ |
| description | The causes of nigrostriatal cell death in idiopathic Parkinson’s disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezuelae were found to kill human dopaminergic neurons (LUHMES cells). Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine (C10H11NO2S; 2-[4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]phenol) and confirmed this finding by chemical re-synthesis. This 2-hydroxyphenyl-thiazoline compound was previously shown to be a product of a wide-spread biosynthetic cluster also found in the human microbiome and in several pathogens. Aerugine triggered half-maximal dopaminergic neurotoxicity at 3–4 µM. It was less toxic for other neurons (10–20 µM), and non-toxic (at <100 µM) for common human cell lines. Neurotoxicity was completely prevented by several iron chelators, by distinct anti-oxidants and by a caspase inhibitor. In the Caenorhabditis elegans model organism, general survival was not affected by aerugine concentrations up to 100 µM. When transgenic worms, expressing green fluorescent protein only in their dopamine neurons, were exposed to aerugine, specific neurodegeneration was observed. The toxicant also exerted functional dopaminergic toxicity in nematodes as determined by the “basal slowing response” assay. Thus, our research has unveiled a bacterial metabolite with a remarkably selective toxicity toward human dopaminergic neurons in vitro and for the dopaminergic nervous system of Caenorhabditis elegans in vivo. These findings suggest that microbe-derived environmental chemicals should be further investigated for their role in the pathogenesis of Parkinson's disease. |
| first_indexed | 2024-03-11T18:23:14Z |
| format | Article |
| id | doaj.art-98f6e31215e34f1eb4609a9fec3612e4 |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-03-11T18:23:14Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-98f6e31215e34f1eb4609a9fec3612e42023-10-15T04:36:32ZengElsevierEnvironment International0160-41202023-10-01180108229Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegenerationAnna-Katharina Ückert0Sina Rütschlin1Simon Gutbier2Nathalie Christine Wörz3Mahfuzur R. Miah4Airton C. Martins5Isa Hauer6Anna-Katharina Holzer7Birthe Meyburg8Ann-Kathrin Mix9Christof Hauck10Michael Aschner11Thomas Böttcher12Marcel Leist13In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457 Konstanz, GermanyDepartment of Chemistry, Konstanz Research School Chemical Biology, Zukunftskolleg, University of Konstanz, 78457 Konstanz, GermanyIn vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457 Konstanz, GermanyFaculty of Chemistry, Institute for Biological Chemistry & Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystems Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090 Vienna, Austria; Doctoral School in Chemistry (DoSChem), University of Vienna, 1090 Vienna, AustriaDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, 10641 Bronx, NY, United StatesDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, 10641 Bronx, NY, United States; Department of Neuroscience, Albert Einstein College of Medicine, 10641 Bronx, NY, United StatesIn vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457 Konstanz, GermanyIn vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457 Konstanz, GermanyIn vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457 Konstanz, GermanyLehrstuhl Zellbiologie, Universität Konstanz, Universitätsstraße 10, Postablage 621, 78457 Konstanz, GermanyLehrstuhl Zellbiologie, Universität Konstanz, Universitätsstraße 10, Postablage 621, 78457 Konstanz, GermanyDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, 10641 Bronx, NY, United States; Department of Neuroscience, Albert Einstein College of Medicine, 10641 Bronx, NY, United StatesDepartment of Chemistry, Konstanz Research School Chemical Biology, Zukunftskolleg, University of Konstanz, 78457 Konstanz, Germany; Faculty of Chemistry, Institute for Biological Chemistry & Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystems Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090 Vienna, Austria; Corresponding author at: Faculty of Chemistry, Institute for Biological Chemistry & Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystems Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090 Vienna, Austria.In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz, 78457 Konstanz, GermanyThe causes of nigrostriatal cell death in idiopathic Parkinson’s disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezuelae were found to kill human dopaminergic neurons (LUHMES cells). Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine (C10H11NO2S; 2-[4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]phenol) and confirmed this finding by chemical re-synthesis. This 2-hydroxyphenyl-thiazoline compound was previously shown to be a product of a wide-spread biosynthetic cluster also found in the human microbiome and in several pathogens. Aerugine triggered half-maximal dopaminergic neurotoxicity at 3–4 µM. It was less toxic for other neurons (10–20 µM), and non-toxic (at <100 µM) for common human cell lines. Neurotoxicity was completely prevented by several iron chelators, by distinct anti-oxidants and by a caspase inhibitor. In the Caenorhabditis elegans model organism, general survival was not affected by aerugine concentrations up to 100 µM. When transgenic worms, expressing green fluorescent protein only in their dopamine neurons, were exposed to aerugine, specific neurodegeneration was observed. The toxicant also exerted functional dopaminergic toxicity in nematodes as determined by the “basal slowing response” assay. Thus, our research has unveiled a bacterial metabolite with a remarkably selective toxicity toward human dopaminergic neurons in vitro and for the dopaminergic nervous system of Caenorhabditis elegans in vivo. These findings suggest that microbe-derived environmental chemicals should be further investigated for their role in the pathogenesis of Parkinson's disease.http://www.sciencedirect.com/science/article/pii/S0160412023005020Dopaminergic neurodegenerationStreptomyces venezuelaeBacterial toxinFerroptosisCaenorhabditis elegansParkinson’s disease |
| spellingShingle | Anna-Katharina Ückert Sina Rütschlin Simon Gutbier Nathalie Christine Wörz Mahfuzur R. Miah Airton C. Martins Isa Hauer Anna-Katharina Holzer Birthe Meyburg Ann-Kathrin Mix Christof Hauck Michael Aschner Thomas Böttcher Marcel Leist Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration Environment International Dopaminergic neurodegeneration Streptomyces venezuelae Bacterial toxin Ferroptosis Caenorhabditis elegans Parkinson’s disease |
| title | Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration |
| title_full | Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration |
| title_fullStr | Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration |
| title_full_unstemmed | Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration |
| title_short | Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration |
| title_sort | identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration |
| topic | Dopaminergic neurodegeneration Streptomyces venezuelae Bacterial toxin Ferroptosis Caenorhabditis elegans Parkinson’s disease |
| url | http://www.sciencedirect.com/science/article/pii/S0160412023005020 |
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