A Microbial Metabolite can Harm Dopaminergenic Neurons

The standard view of Parkinson's disease is that misfolding of α-synuclein occurs in the gut or brain, and then spreads in a prion-like manner to cause widespread dysfunction and cell death throughout the brain. The most vulnerable cells are dopaminergic neurons, and their destruction causes the most evident symptoms of the disease. Some people have a greater risk of Parkinson's disease than others. The most studied vulnerabilities are genetic variants that appear to make dopaminergic neurons even more vulnerable to stress. Environmental factors may also attack this population of neurons: here, researchers note that a soil bacteria sometimes found in the gut microbiome can produce a metabolite that is toxic to dopaminergic neurons.

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 in vitro. Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine and confirmed this finding by chemical re-synthesis.

This 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.

Link: https://doi.org/10.1016/j.envint.2023.108229