Manganese-Induced Parkinsonism Is Not Idiopathic Parkinson’s Disease: Environmental and Genetic Evidence

Abstract

Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder.

Environmental exposure to manganese in air: Associations with tremor and motor function

“…In PD, dopamine levels are depleted through nigrostriatal dopamine neuron degeneration; with Mn overexposure, pathology appears to be related to postsynaptic impairment to the nigrostriatal system (Calne et al, 1994). In a current paper addressing this issue, Guilarte and Gonzales (2015) suggest the damage from Mn may not be linked to midbrain dopaminergic neuron cell loss, which is the pathophysiological process in PD. Despite these differences, the functional result of neuropathology in both disorders is considered similar and involves disruption of the pathways connecting the basal ganglia to the prefrontal cortex, which govern purposeful movement and behavioral and motor inhibition.…”

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

“…In addition, manganism is not responsive to treatment with DA precursor levodopa, a drug used in the early stages of PD. Furthermore, manganism presents with a lack of resting tremor but consistent presence of dystonia [33–35]. …”

Medication use associated with exposure to manganese in two Ohio towns

“…Symptoms at that point are similar to Parkinson’s disease and include dystonia, gait abnormalities, bradykinesia, and rigidity (Guilarte 2010; Guilarte & Gonzales 2015). However, as the literature indicates, motor disturbances in Mn-exposed persons are resistant to levodopa medication (Guilarte et al 2006) and Mn-affected persons may use more medications to ameliorate their health problems.…”