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Review
. 2015:35:71-108.
doi: 10.1146/annurev-nutr-071714-034419. Epub 2015 May 13.

Manganese Is Essential for Neuronal Health

Kyle J Horning  1 , Samuel W Caito, K Grace Tipps, Aaron B Bowman, Michael Aschner
Affiliations
Review

Manganese Is Essential for Neuronal Health

Kyle J Horning et al. Annu Rev Nutr. 2015.

Abstract

The understanding of manganese (Mn) biology, in particular its cellular regulation and role in neurological disease, is an area of expanding interest. Mn is an essential micronutrient that is required for the activity of a diverse set of enzymatic proteins (e.g., arginase and glutamine synthase). Although necessary for life, Mn is toxic in excess. Thus, maintaining appropriate levels of intracellular Mn is critical. Unlike other essential metals, cell-level homeostatic mechanisms of Mn have not been identified. In this review, we discuss common forms of Mn exposure, absorption, and transport via regulated uptake/exchange at the gut and blood-brain barrier and via biliary excretion. We present the current understanding of cellular uptake and efflux as well as subcellular storage and transport of Mn. In addition, we highlight the Mn-dependent and Mn-responsive pathways implicated in the growing evidence of its role in Parkinson's disease and Huntington's disease. We conclude with suggestions for future focuses of Mn health-related research.

Keywords: blood-brain barrier; cofactor; homeostasis; intracellular trafficking; metal transport; neurodevelopment.

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Figures

Figure 1
Figure 1
Known transporters and channels permeable to Mn within the brain and their cellular localizations. Other metals with affinities for each transporter are also listed. Figure is not drawn to scale. Abbreviations: DAT, dopamine transporter; ER; endoplasmic reticulum; Gln, glutamine; Glu, glutamate; GS, glutamine synthetase; Mn, manganese; MT, metallothionein; NCX, sodium-calcium exchanger; OAT, organic anion transporter; SOCC, store-operated calcium channel.
Figure 2
Figure 2
Mechanism of Mn detection via SPCA1 and GPP130. Endocytosed vesicles containing GPP130 are typically sorted directly to the late Golgi. SPCA1 transports Mn into the Golgi complex. In the presence of Mn and GPP130, vesicles are either guided to lysosomes, where Mn is then sequestered, or are brought to the membrane, where Mn is then exocytosed. Abbreviations: GPP, cis-Golgi glycoprotein; Mn, manganese; SPCA1, secretory pathway Ca2+-ATPase isoform 1.
Figure 3
Figure 3
Glutamine synthetase activity is diminished in Huntington’s disease (HD). Glutamine synthetase is an Mn-dependent enzyme. Efficient glutamate uptake by astrocytes relies on glutamine synthetase. In HD, where cellular Mn is reduced, impaired glutamine synthetase activity inhibits glutamate uptake. Abbreviations: Gln, glutamine; Glu, glutamate; GS, glutamine synthetase; Mn, manganese.
Figure 4
Figure 4
Mn-ATM-p53 pathway. Following doubled-stranded DNA damage, ATM is activated by Mn to phosphorylate p53 and Mre11 of the MRN complex. The MRN complex is then able to repair the DNA damage. Abbreviations: ATM, ataxia telangiectasia mutated; Mn, manganese; MRN, Mre11, Rad50, Nbs1.
Figure 5
Figure 5
Inflammatory response induced by Mn. Mn exposure leads to the production of NF-κB and p38 in astrocytes, which increases reactive oxygen species. Inflammatory markers (IL-6, IL-1β, and TNF-α) are produced by microglia following Mn exposure. In the presence of these markers and Mn, neurons have been found to increase expression of the Mn-permeable ZIP14 and decrease expression of the Mn exporter SLC30A10. Abbreviations: IL-1β/6, interleukin-1β/6; Mn, manganese; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ROS, reactive oxygen species; SLC, solute carrier; TNFα; tumor necrosis factor-alpha.
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