This review synthesizes clinical, epidemiological, and experimental findings to explore the underlying mechanisms, contributing factors, and current treatments of manganese-induced parkinsonism. It also reviews preventative and therapeutic approaches to highlight future research directions.

Manganese is essential for brain development and function, though excessive exposure to high concentrations is known to cause neurotoxicity and is associated with manganese-induced parkinsonism.

We conducted a narrative review (PubMed, ScienceDirect, institutional databases) using search terms including “manganese neurotoxicity” and “manganese AND parkinsonism,” and included clinical, mechanistic, and epidemiological studies through 2025.

Manganese toxicity can occur with mutations in SLC30A10 and SLC39A14, impaired hepatic clearance, or industrial, ephedrone, and NMC battery exposure. Other transporters, such as SNAT3, GLAST, and GLT-1, are affected by PKC signaling and YY1 transcription upregulation. Accumulation of manganese may cause dopamine oxidation and neurotoxicity. Manganese overexposure increases oxidative stress, sphingomyelinase activity, lipid metabolism disorders, and mitochondrial dysfunction involving PINK1, ZNF746, and KAT2A/H3K36ac. It activates the cGAS-STING and NF-κB pathways, reduces SIRT1 activity, induces S-nitrosylation, alters Na⁺, K⁺-ATPase activity, and increases α-synuclein expression. CircREST downregulation promotes apoptosis, while MEK5–ERK5 signaling and M2 microglial polarization provide partial neuroprotection.

Therapeutically, Levodopa may provide limited symptomatic relief but is often ineffective. Sediment-bound manganese is less bioavailable, reducing neurotoxicity. Chelation therapy with CaNa₂EDTA or para-aminosalicylic acid (PAS), therapeutic plasma exchange (TPE), and complementary treatments such as Echium amoenum extract, vinpocetine, punicalagin, niacin, vitamin E, dendrobium nobile alkaloids (DNLA), resveratrol, curcumin, and sesame oil demonstrate neuroprotective and antioxidant effects by reducing oxidative stress and improving motor and cognitive function.

The mechanisms of manganese-induced cellular and neurological dysfunction are actively being investigated. Affected pathways—such as PKCδ-mediated apoptosis, NF-κB and cGAS-STING inflammation, YY1 transcriptional regulation, BBB disruption, histone acetylation, and CNS transporter changes—highlight potential therapeutic targets. Combining neuroprotective, antioxidant, and anti-inflammatory approaches with chelation and plasma exchange may improve outcomes.