Manganese and its role in Parkinson's disease: from transport to neuropathology

Abstract

The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147-154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009).

Fig. 1

GABA biology during Mn overload. This simple schematic of the basal ganglia represents the potential consequences of the increased extracellular GABA concentrations in the striatum due to Mn exposure. (1) Increased extracellular GABA concentrations in the striatum would reduce the activity of the GABA striatopallidal projection neurons (Anderson et al. 2008) (2) (dotted line). This reduction in activity would (3) increase the GABAergic inhibitory firing from the globus pallidus (GP) to the subthalamic nucleus (STN) (heavy black line), in turn (4) decreasing the excitatory glutamatergic firing from this region to the substantia nigra (SN) (dotted line). (5) Decreased glutamatergic excitation in the substantia nigra, along with decreased GABAergic inhibition from the striatonigral projection neurons (dotted line) and decreased protein expression of GAT-1 and GABA_B (Anderson et al. 2008) would lead to a dysregulation of dopaminergic firing to the striatum (alternating line)

Fig. 2

A welder before chelation therapy. Brain MRI, sagittal (a) and axial (b) T1-weighted sequences showing a definite hyper signal of globi pallidi (from Herrero Hernández et al. 2006)