Manganese homeostasis in the nervous system

Abstract

Manganese (Mn) is an essential heavy metal that is naturally found in the environment. Daily intake through dietary sources provides the necessary amount required for several key physiological processes, including antioxidant defense, energy metabolism, immune function and others. However, overexposure from environmental sources can result in a condition known as manganism that features symptomatology similar to Parkinson's disease (PD). This disorder presents with debilitating motor and cognitive deficits that arise from a neurodegenerative process. In order to maintain a balance between its essentiality and neurotoxicity, several mechanisms exist to properly buffer cellular Mn levels. These include transporters involved in Mn uptake, and newly discovered Mn efflux mechanisms. This review will focus on current studies related to mechanisms underlying Mn import and export, primarily the Mn transporters, and their function and roles in Mn-induced neurotoxicity. Though and essential metal, overexposure to manganese may result in neurodegenerative disease analogous to Parkinson's disease. Manganese homeostasis is tightly regulated by transporters, including transmembrane importers (divalent metal transporter 1, transferrin and its receptor, zinc transporters ZIP8 and Zip14, dopamine transporter, calcium channels, choline transporters and citrate transporters) and exporters (ferroportin and SLC30A10), as well as the intracellular trafficking proteins (SPCA1 and ATP12A2). A manganese-specific sensor, GPP130, has been identified, which affords means for monitoring intracellular levels of this metal.

Keywords: Parkinson's disease; manganese; transport.

Figure

In cells, the intracellular Mn level is tightly regulated by transporters on the cell surface and the intracellular transporters localized on the membrane of internal organelles. On the cell surface, DMT-1, DAT, ZIP8/ZIP14, citrate transporters and Ca channels facilitate Mn²⁺ influx in to the cytosol, while SLC30A10 and ferroportin mediate efflux of Mn²⁺. Mn³⁺ can be directly transported in cells through Tf/TfR. In addition, Mn³⁺ also enters cells through Tf/TfR mediated endocytosis and finally released into cytoplasm as Mn²⁺ by DMT1. When the cytosolic Mn reaches a threshold, SPCA1 on the Golgi membrane and ATP13A2 on the lysosome membrane will transport Mn into the Golgi and lysosomes, respectively, which facilitate Mn²⁺ efflux into the extracellular matrix.