Manganese is an essential trace mineral that plays a crucial role in several important bodily functions, including the metabolism of amino acids, cholesterol, glucose, and carbohydrates, as well as the formation of connective tissue and bones. It also plays a vital role in the body’s defense against oxidative stress, due to its involvement in the function of key enzymes like manganese superoxide dismutase (MnSOD). However, while manganese is necessary for good health, both deficiency and excessive exposure can lead to significant health problems. Maintaining an appropriate level of manganese is essential for optimal functioning, but exposure to high levels of this mineral—especially in certain occupational settings—can be harmful to the central nervous system.
Manganese and the Nervous System: Health Risks
For most people, manganese intake from a balanced diet is sufficient to meet the body’s needs. Common dietary sources of manganese include whole grains, nuts, seeds, legumes, and leafy green vegetables. However, problems arise when individuals are exposed to higher-than-normal levels of manganese, either through environmental or occupational sources. In some settings, such as in mining, welding, or areas with contaminated drinking water, individuals may be exposed to elevated levels of manganese over extended periods.
When manganese exposure exceeds safe levels, it can become toxic, particularly to the central nervous system. Chronic manganese exposure has long been linked to the development of Parkinsonism, a condition that resembles Parkinson’s disease but is caused by a different set of mechanisms. This condition, known as manganism, is characterized by symptoms such as tremors, muscle rigidity, cognitive disturbances, and altered motor skills, all of which mimic Parkinson’s disease.
The Mechanisms of Manganese-Induced Damage
The neurological damage caused by chronic manganese exposure has been a subject of ongoing research, with new studies shedding light on the mechanisms by which manganese affects brain function. A significant study published in Science Signaling offers new insights into how manganese inflicts damage to nerve cells and explores potential therapeutic avenues to mitigate its harmful effects. This study employs both model systems, such as Drosophila melanogaster (fruit flies), and human nerve cells derived from induced pluripotent stem cells (iPSCs) to uncover the pathways of manganese toxicity.
Dr. Sarkar Souvarish, the lead author of the study and an assistant professor at the University of Rochester Medical Center (URMC), described the new findings, explaining that manganese exposure is known to cause a variety of neurological problems, particularly in individuals who are exposed to high levels of the mineral in their occupations. Welding fumes and certain sources of rural drinking water have been identified as significant contributors to these elevated levels of manganese.
In the study, the researchers used advanced techniques, such as untargeted metabolomics combined with high-resolution mass spectrometry and cheminformatics computing, to study manganese’s effects in model systems. Their research revealed how manganese causes damage to the brain by binding with alpha-synuclein, a protein that is crucial for the regulation of synaptic vesicles and neurotransmitter release. Manganese binding to this protein causes it to misfold, leading to the accumulation of toxic aggregates in the brain—an early hallmark of several neurodegenerative diseases, including Parkinson’s disease.
Modeling Manganese Exposure: The Fruit Fly and Human Neurons
To better understand the impact of manganese exposure on the nervous system, the researchers used the fruit fly (Drosophila) as a model organism. The fruit fly is a useful tool in neurological research due to its relatively simple nervous system and genetic similarities to humans. The team developed a model that mimicked occupational manganese exposure, exposing the flies to high levels of the metal. The results showed that manganese caused several detrimental effects, including:
- Motor deficits: The flies displayed difficulty in movement and coordination, resembling the motor symptoms seen in Parkinsonism.
- Mitochondrial dysfunction: Manganese exposure disrupted mitochondrial function, which is critical for cellular energy production.
- Lysosomal dysfunction: Manganese exposure impaired lysosomal activity, which is important for the breakdown and recycling of cellular waste.
- Neuronal loss: The exposure led to the death of neurons, which are vital for brain function and communication.
- Reduced lifespan: Flies exposed to manganese showed a shorter lifespan, demonstrating the long-term effects of chronic exposure.
The team also validated these findings using human dopaminergic neurons derived from iPSCs. These neurons are particularly relevant because the loss of dopamine-producing neurons is a key feature of Parkinson’s disease and other Parkinsonian syndromes. The results were striking—manganese selectively damaged these neurons, leading to cell death, reduced dopamine production, and other neurodegenerative effects.
Biotin: A Potential Protective Agent
Interestingly, the study also explored the potential for biotin, a water-soluble B-vitamin, to counteract the damage caused by manganese exposure. Biotin, which is synthesized by gut bacteria, plays an important role in several physiological processes, including the metabolism of carbohydrates, fats, and proteins. It has also been recognized for its ability to enhance dopamine production, which is crucial for maintaining motor function and cognitive health.
The researchers found that biotin supplementation had a protective effect in both the fruit fly model and the human iPSC-derived neurons. In flies, biotin reversed many of the neurotoxic effects of manganese exposure, improving motor function, enhancing mitochondrial activity, and reducing neuronal loss. Similarly, biotin supplementation in human dopaminergic neurons improved mitochondrial function and prevented the death of dopamine-producing cells.
These findings suggest that biotin could serve as a potential therapeutic strategy to mitigate manganese-induced neurodegeneration. The safety and tolerability of biotin in humans make it an attractive candidate for further research. Moreover, biotin-rich prebiotics or biotin-producing probiotics could provide non-pharmacological intervention options to reduce the risks associated with manganese exposure. However, the study’s authors emphasize that more research is needed to fully understand how biotin might be used as a treatment for manganese toxicity.
Understanding the Connection Between Manganese and Parkinsonism
The results of this study underscore the growing recognition that Parkinsonism and related neurodegenerative diseases, like Parkinson’s disease, are multisystem disorders. While the loss of dopamine-producing neurons in the brain is central to Parkinson’s disease, the disorder also involves changes in other systems, including the gut and the microbiome. Some researchers have hypothesized that disruptions in the gut microbiome may contribute to the development of Parkinson’s disease, with early symptoms sometimes emerging in the gut before spreading to the brain. The connection between manganese exposure, gut microbiota, and neurodegeneration presents an exciting area for further investigation.
The study also highlights the importance of environmental and occupational exposures to toxic metals, which can significantly increase the risk of neurological conditions like Parkinsonism. Given the increasing industrialization and use of chemicals in various sectors, understanding the role of environmental factors in neurodegenerative diseases is crucial for both public health and occupational safety.
Conclusion: The Path Forward
This research on manganese toxicity and its impact on the central nervous system has opened up new avenues for potential interventions. While manganese remains an essential nutrient at low levels, chronic exposure to elevated levels can lead to serious health problems, particularly in individuals working in industries where exposure is common. By uncovering the mechanisms by which manganese damages neurons, this study offers a deeper understanding of how toxic metals contribute to the development of Parkinsonism and similar neurodegenerative diseases.
The finding that biotin supplementation could mitigate some of the damage caused by manganese exposure is particularly promising, suggesting that simple, non-pharmacological interventions could potentially offer a therapeutic option for those at risk of manganese toxicity. However, further research is necessary to determine the effectiveness and safety of biotin in this context.
As our understanding of manganese’s effects on the brain and the potential for protective interventions grows, this research may help inform public health policies, occupational safety regulations, and treatment strategies for those affected by chronic manganese exposure.
Reference: Biotin rescues manganese-induced Parkinson’s disease phenotypes and neurotoxicity, Science Signaling (2025). DOI: 10.1126/scisignal.adn9868