While manganese is an essential mineral involved in many bodily functions, both deficiency and excessive exposure can cause health issues. Maintaining a balanced diet typically provides sufficient manganese for most individuals; however, high levels of exposure can be toxic, particularly to the central nervous system. Chronic manganese exposure may result in a condition known as manganism, characterized by symptoms resembling Parkinson's disease, including tremors, muscle stiffness, and cognitive disturbances.
New research published in Science Signaling employs model systems and human nerve cells to show the mechanisms by which manganese inflicts damage to the central nervous system. The study also suggests that the vitamin biotin may have a protective effect, potentially mitigating manganese-induced damage.
"Exposure to neurotoxic metals like manganese has been linked to the development of Parkinsonism," said Sarkar Souvarish, PhD, an assistant professor at the University of Rochester Medical Center (URMC) Departments of Environmental Medicine and Neuroscience and lead author of the study. "In this study, we applied untargeted metabolomics using high-resolution mass spectrometry and advanced cheminformatics computing in a newly developed model of parkinsonism, leading us to the discovery of biotin metabolism as a modifier in manganese-induced neurodegeneration."
Understanding manganese's damage to the brain
Chronic occupational and environmental exposure to manganese, commonly from welding fumes and some sources of rural drinking water, increases the risk of Parkinsonian syndrome, which involves similar but distinct neurological symptoms from Parkinson's disease. Manganese has been previously shown to bind with the protein alpha-synuclein, causing it to misfold and accumulate in the brain.
Using the fruit fly Drosophila, researchers developed a model that mimics occupational manganese exposure in humans and found that manganese induced motor deficits, mitochondrial and lysosomal dysfunction, neuronal loss, and reduced lifespan in flies.
The team validated these findings using human dopaminergic neurons derived from induced pluripotent stem cells (iPSC) and demonstrated that manganese exposure selectively damages these cells. The loss of dopamine-producing cells is a hallmark of Parkinson's disease and Parkinsonian syndrome.
Biotin to the rescue?
The research indicates that B vitamin biotin, a micronutrient synthesized by gut bacteria, enhances dopamine production in the brain. Biotin supplementation reversed neurotoxicity in flies and iPSC-derived neurons, improving mitochondrial function and reducing cell loss.
This finding aligns with a growing scientific recognition that Parkinson's is a multisystem disorder, with early symptoms often emerging in the gut, and that changes in the gut microbiome may contribute to the disease.
"Biotin supplementation shows potential as a therapeutic strategy to mitigate manganese-induced neurodegeneration, and the safety and tolerability of biotin in humans make it a promising candidate for further exploration," said Souvarish. "Biotin-rich prebiotics or biotin-producing probiotics could provide non-pharmacological intervention options, but more studies have to performed."
Additional co-authors include Pablo Reina-Gonzalez with URMC, Gali Maor with Harvard University, and Yunjia Lai and Gary W. Miller with Columbia University. The research was supported with funding from the National Institutes of Health.
