METALS IN MEDICINE AND THE ENVIRONMENT

Manganism is a neurodegenerative disorder resulting from chronic expose to abnormally high levels of the essential element manganese. The symptoms very closely resemble those of Parkinson’s disease, including bradykinesia (slow movement), dystonia (sustained muscle contractions), and disturbance of gait. As one would expect (just as in Parkinson’s), manganese toxicity is most severe in the basal ganglia, which is responsible for initiating and modulating movements. However, manganese exposure affects a different part of the basal ganglia circuit. Parkinson’s disease results from the degeneration of dopaminergic axons projecting from the substantia nigra to the striatum. Dopamine normally provides an excitatory input to the caudate/putamen, the area that receives the majority of the motor information in the basal ganglia. The projections from the caudate/putamen to the globus pallidus are inhibitory, and as such this degeneration of the nigrostriatal pathway results in a decreased inhibition of neurons in the globus pallidus. The projections from the globus pallidus to the thalamus are also inhibitory, so decreased inhibition in the globus pallidus actually results in an increased inhibition to the thalamus. The signal from the thalamus to the primary motor cortex is thus reduced and results in a deficit in the initiation of movement. In contrast to Parkinson’s, Manganism symptoms result from the degeneration of inhibitory GABAergic input from the globus pallidus to the thalamus. This then results in an overall decreased inhibition of the thalamus, and thus thalamocortical signaling is increased. So the two diseases both result in similar movement disorders, but by affecting different parts of the same pathway, and producing opposite net changes in the balance of thalamic excitation and inhibition. (1)

mn basal ganglia

Manganism is caused primarily by the inhalation of trace amount of manganese rather than by absorption in the gastrointestinal tract (where it is relatively impermeable). Entry into the brain can occur in primarily via two pathways. First, it may be inhaled through the lungs and absorbed into the blood stream. From there it is able to cross the blood-brain barrier via specific transport proteins.(2) The other possible route is directly through the olfactory system. Manganese can be taken up by olfactory sensory neurons in the epithelium and actually transported trans-synaptically throughout the brain. These toxic inhalation routes make Manganism more prevalent among occupations such as welders and miners, where fumes containing MnO2 are especially concentrated. (3)

The actual mechanism by which manganese targets these individual neurons is not yet known. Even the cellular entry mechanisms are not fully understood. Two main pathways have been proposed: a transferrin-dependent and -independent route, both of which operate similarly to those for iron transport.(4,5)  The transferrin- dependent pathway involves the binding of Mn3+ to the tranferrin protein. This complex then binds to the tranferrin receptor, is invaginated by an endosome, and then dissociated and reduced to Mn2+ in the acidic environment. The transferrin-independent pathway can be mediated by a number of different channels such as the divalent metal transporter 1 (DMT1), a voltage-gated Ca2+ channel, or even the glutamate-gated n-methyl-d-aspartate (NMDA) receptor. (5)

Mn transport

Such mechanisms are most likely used in combination and might determine the differing susceptibility not only between cell types but also between individuals. These remaining questions will be the topics of much research to come.
           
Resources

Symptoms of manganism and FAQ

Metals and neurodegeneration

Manganism research: history, critique, and unanswered questions

References

(1) D. P. Perl and C. W. Olanow. The neuropathology of manganese-induced parkinsonism. J Neuropathol Exp Neurol 66 (8), 675 (2007).

(2) M. Aschner. Manganese: Brain transport and emerging research needs. Environ Health Perspect 108 Suppl 3, 429 (2000).

(3) A. B. Santamaria, C. A. Cushing, J. M. Antonini et al. State-of-the-science review: Does manganese exposure during welding pose a neurological risk? J Toxicol Environ Health B Crit Rev 10 (6), 417 (2007).

(4) J. A. Roth and M. D. Garrick. Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese. Biochem Pharmacol 66 (1), 1 (2003).

(5) J. A. Roth. Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination. Biol Res 39 (1), 45 (2006).

Author: James Corson