Role of Astrocytes in Manganese Neurotoxicity Revisited

Abstract

Manganese (Mn) overexposure is a public health concern due to its widespread industrial usage and the risk for environmental contamination. The clinical symptoms of Mn neurotoxicity, or manganism, share several pathological features of Parkinson's disease (PD). Biologically, Mn is an essential trace element, and Mn in the brain is preferentially localized in astrocytes. This review summarizes the role of astrocytes in Mn-induced neurotoxicity, specifically on the role of neurotransmitter recycling, neuroinflammation, and genetics. Mn overexposure can dysregulate astrocytic cycling of glutamine (Gln) and glutamate (Glu), which is the basis for Mn-induced excitotoxic neuronal injury. In addition, reactive astrocytes are important mediators of Mn-induced neuronal damage by potentiating neuroinflammation. Genetic studies, including those with Caenorhabditis elegans (C. elegans) have uncovered several genes associated with Mn neurotoxicity. Though we have yet to fully understand the role of astrocytes in the pathologic changes characteristic of manganism, significant strides have been made over the last two decades in deciphering the role of astrocytes in Mn-induced neurotoxicity and neurodegeneration.

Keywords: Astrocyte; Glutamate; Glutamine; Manganese; Neurotoxicity.

Fig. 1

Mn deregulates Gln and Glu transporters expression and function by PKC pathway activation. Glu released from synaptic terminals is taken up by surrounding astrocytes via Glu transporters and converted to Gln via the reaction mediated by GS. A proportion of Gln is released into the extracellular space by Gln carriers, with a predominant role of system N. In addition to system N, release of Gln from astrocytes is mediated by transporters belonging to systems L and ASC. Extracellular Gln is taken up into GABAergic and glutamatergic neurons by the unidirectional system A transporters. Once in neurons, Gln serves as a substrate for the mitochondrial enzyme, PAG for the synthesis of Glu, which supply neurotransmission pool of Glu, or can be converted to GABA by GAD or to αKG by GDH. Excessive levels of Mn deregulates processes related to the Gln and Glu transporter expression and function by PKC pathway activation. αKG αketoglutaric acid, GABA γ-aminobutyric acid, GAD glutamate decarboxylase, GDH glutamate dehydrogenase, Gln glutamine, Glu glutamate, NAA neutral amino acids, PAG phosphate activated glutaminase, PKCα protein kinase C alpha, PKCδ protein kinase C delta, TCA tricarboxylic acid