Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

Abstract

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).

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

“…Non-motor symptoms have also been associated with excessive Mn exposure (Guilarte et al, 2008b;Aschner et al, 2009;Guilarte, 2013). Neuropathological changes in frontal cortex of non-human primates as a consequence of Mn exposure have also been described (Verina et al, 2013).…”

Shiga toxins

“…Interestingly, Mn-ions were found to protect against the Shiga toxin in mice by redirecting it to the degradative pathway [161,162], but no protection was provided against Stx2 under the same conditions [163]. Also, protection against Shiga toxins may depend on cell type and the mouse strain [164], and caution should be exerted since Mn-ions are neurotoxic [164,165]. Quite recently, chemical compound screens have provided us with drugs that seem to inhibit endosome-to-Golgi transport and that protect against both the plant toxin ricin and Shiga toxin [166][167][168].…”

Differential interaction of hGDH1 and hGDH2 with manganese: Implications for metabolism and toxicity

“…It is of interest that the clinical effects of Mn neurotoxicity resemble Parkinson's disease (Aschner et al, 2009). In this respect, it has been shown that a rare variant of the hGDH2 gene leads to earlier age of onset in Parkinson's disease patients (Plaitakis et al, 2010).…”