Manganese-Induced Neurotoxicity and Neurodegenerative Disorders

Manganese (Mn) is an essential trace element that serves as a cofactor for numerous enzymes, including mitochondrial superoxide dismutase, and supports neurotransmitter synthesis, energy metabolism and antioxidant defence. However, elevated Mn exposure—whether through occupational inhalation, contaminated drinking water or impaired excretion—can lead to its accumulation in the basal ganglia and other brain regions, triggering a spectrum of adverse effects collectively termed “manganism.” Clinically, manganism presents with motor and cognitive deficits resembling Parkinson’s disease, but with distinct neuropathological and symptomatic profiles. Molecular mechanisms implicated in Mn neurotoxicity include mitochondrial dysfunction, oxidative stress, protein misfolding, dopaminergic and cholinergic dysregulation, and chronic neuroinflammation. Glial cells, particularly microglia and astrocytes, play a central role by amplifying inflammatory cascades that exacerbate neuronal injury. Genetic mutations in Mn transporters further disrupt systemic and cerebral Mn homeostasis, underscoring the interplay between environmental and hereditary risk factors. Current research aims to refine biomarkers of exposure, elucidate cellular pathways of toxicity and develop targeted interventions—ranging from metal chelators to neuroprotective agents—to mitigate Mn-related neurodegeneration and preserve long-term neurological health.

Research from Nature Portfolio

Recent studies have unveiled critical insights into the molecular machinery governing Mn distribution and its impact on the nervous system. One investigation characterised the SLC39A8 transporter in intestinal epithelia, demonstrating that its deletion markedly reduces systemic Mn levels and alters lipid-mediated barrier integrity, thereby refining our understanding of whole-body Mn handling. Complementary work on SLC39A14 mutations revealed that defective transporter function leads to rapid childhood-onset parkinsonism–dystonia, with pronounced Mn accumulation in brain tissue. Animal models bearing SLC39A14 loss-of-function mutations exhibit motor impairments and altered locomotor activity, while chelation therapy effectively lowers blood Mn and induces clinical improvement. Together, these findings highlight the central role of specific ZIP family transporters in maintaining Mn homeostasis and illustrate the therapeutic potential of modulating transporter activity or metal clearance in preventing neurotoxicity.

Manganese-Induced Neurotoxicity and Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in manganese-induced neurotoxicity and neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Divalent metal transporter-1 (DMT1): A membrane protein that mediates cellular uptake of Mn and other divalent metals.

Manganism: A neurological syndrome caused by chronic Mn overexposure, characterised by motor and cognitive impairments.

Chelation therapy: Treatment using agents that bind excess metals to facilitate their excretion and reduce tissue accumulation.

Basal ganglia: Subcortical brain nuclei involved in motor control and cognitive functions, prone to Mn accumulation.

Neuroinflammation: Immune activation in the central nervous system involving microglia and astrocytes that can exacerbate neuronal injury.

Mitochondrial dysfunction: Impairment of mitochondrial energy production and redox balance, a key driver of Mn-induced oxidative stress.

References

1. Manganese Superoxide Dismutase: Guardian of the Powerhouse. International Journal of Molecular Sciences (2011).
2. Manganese-Induced Parkinsonism and Parkinson’s Disease: Shared and Distinguishable Features. International Journal of Environmental Research and Public Health (2015).
3. Manganese-Induced Neurotoxicity: New Insights Into the Triad of Protein Misfolding, Mitochondrial Impairment, and Neuroinflammation. Frontiers in Neuroscience (2019).
4. Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. Journal of Neuroinflammation (2017).
5. “Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”. BMC Pharmacology and Toxicology (2016).
6. The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease. Nature Communications (2024).
7. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia. Nature Communications (2016).