Parkinson’s Puzzle G20._ _
Could the trillions of bacteria living in our guts be contributing to neurodegenerative diseases like Parkinson's? This unsettling question underpins a trailblazing new study that identifies a bacterial metabolite capable of mirroring the hallmark neuronal destruction seen in Parkinson's disease. While scientists have long suspected environmental factors in the development of Parkinson's, the vast majority of research has focused on pesticides and industrial chemicals. But we may have been looking in the wrong place all along.
The underlying causes of Parkinson’s, a debilitating neurodegenerative condition, still elude scientists. Genetic mutations directly cause a mere 10% of cases. The remaining 90% arise sporadically, with no clear genetic link. Intriguingly, the gut microbiome composition of Parkinson’s patients consistently differs from healthy individuals. And several studies report provocative associations between gut bacteria, their metabolites, and neurological diseases. Could our microbiome prove the missing piece of the Parkinson’s puzzle?
A new study published in Environment International investigates this question. The researchers identified a bacterial metabolite, aerugine, that can severely damage human dopamine-producing neurons — the very neurons decimated in Parkinson’s brains. Introducing this metabolite to worms mirrored neuronal and movement patterns observed in human Parkinson’s patients.
This discovery fundamentally shifts our perspective on Parkinson’s, opening new avenues to finally crack its mysteries. How do microbial metabolites interact with neurons? Could they influence other neurodegenerative diseases? Most critically, can we leverage this knowledge to develop preventative measures and new treatments? While much work lies ahead, these seminal findings promise to revolutionize our understanding of Parkinson’s complex causes.
REFERENCE:
Uckert AK, Rutschlin S, Gutbier S, Worz NC, Miah MR, Martins AC, . . . Leist M (2023) Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration. Environment International, 180:108229. PMID: 37797477; PMCID: PMC10666548. URL: https://www.ncbi.nlm.nih.gov/pubmed/37797477 & https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666548/pdf/nihms-1937915.pdf
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 (C(10)H(11)NO(2)S; 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 microM. It was less toxic for other neurons (10-20 microM), and non-toxic (at <100 microM) 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 microM. 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.
Could the trillions of bacteria living in our guts be contributing to neurodegenerative diseases like Parkinson's? This unsettling question underpins a trailblazing new study that identifies a bacterial metabolite capable of mirroring the hallmark neuronal destruction seen in Parkinson's disease. While scientists have long suspected environmental factors in the development of Parkinson's, the vast majority of research has focused on pesticides and industrial chemicals. But we may have been looking in the wrong place all along.
The underlying causes of Parkinson’s, a debilitating neurodegenerative condition, still elude scientists. Genetic mutations directly cause a mere 10% of cases. The remaining 90% arise sporadically, with no clear genetic link. Intriguingly, the gut microbiome composition of Parkinson’s patients consistently differs from healthy individuals. And several studies report provocative associations between gut bacteria, their metabolites, and neurological diseases. Could our microbiome prove the missing piece of the Parkinson’s puzzle?
A new study published in Environment International investigates this question. The researchers identified a bacterial metabolite, aerugine, that can severely damage human dopamine-producing neurons — the very neurons decimated in Parkinson’s brains. Introducing this metabolite to worms mirrored neuronal and movement patterns observed in human Parkinson’s patients.
This discovery fundamentally shifts our perspective on Parkinson’s, opening new avenues to finally crack its mysteries. How do microbial metabolites interact with neurons? Could they influence other neurodegenerative diseases? Most critically, can we leverage this knowledge to develop preventative measures and new treatments? While much work lies ahead, these seminal findings promise to revolutionize our understanding of Parkinson’s complex causes.
REFERENCE:
Uckert AK, Rutschlin S, Gutbier S, Worz NC, Miah MR, Martins AC, . . . Leist M (2023) Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration. Environment International, 180:108229. PMID: 37797477; PMCID: PMC10666548. URL: https://www.ncbi.nlm.nih.gov/pubmed/37797477 & https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666548/pdf/nihms-1937915.pdf
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 (C(10)H(11)NO(2)S; 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 microM. It was less toxic for other neurons (10-20 microM), and non-toxic (at <100 microM) 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 microM. 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.