Titel
Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration
Autor*in
Anna-Katharina Ückert
In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz
Sina Rütschlin
Department of Chemistry, Konstanz Research School Chemical Biology, Zukunftskolleg, University of Konstanz
Simon Gutbier
In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden foundation, University of Konstanz
... show all
Abstract
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.
Stichwort
Dopaminergic neurodegenerationStreptomyces venezuelaeBacterial toxinFerroptosisCaenorhabditis elegansParkinson’s disease
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
phaidra.univie.ac.at/o:2046239
Erschienen in
Titel
Environment International
Band
180
ISSN
0160-4120
Erscheinungsdatum
2023
Publication
Elsevier BV
Erscheinungsdatum
2023
Zugänglichkeit
Rechte
Rechteangabe
(c) 2023 The Authors
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