Signaling Pathways Involved in Manganese-Induced Neurotoxicity

Abstract

Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP-AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

Keywords: autophagy; insulin-like growth factor (IGF); manganese; neurotoxicity; signaling pathway.

Figure 1

Molecular signaling pathways associated with Mn neurotoxicity. Mn, as an essential trace element, can maintain intracellular stress and promote cellular energy metabolism by increasing glucose uptake. Mn can directly bind to IR/IGFR to activate the insulin/IGF signaling pathway and regulate its downstream components, mainly PI3K/Akt, and cross-regulat the Ras/MAPK, JNK, and p38 signaling pathways (Section 2). Activated AKT can promote protein transport and activate autophagy by regulating mTOR and regulating cell apoptosis by the FOXO signaling pathway. In addition, Mn exposure can activate CREB by activating the Ras/MAPK and p38 signaling pathways, thereby increasing BDNF to inhibit apoptosis. However, prolonged activation of the above pathways may still fail to overcome the cytotoxic effects of Mn and may even elicit adverse downstream events to promote inflammation and cell apoptosis. Mn exposure can overactivate the cCAS-STING, NFκB, and JAK/STAT signaling pathways, as well as inhibit the SIRT signaling pathway, leading to an inflammatory response, which activates NLRP3-CASP1 inflammasome (Section 3). Downregulated SIRT1 can promote mitochondrial damage and apoptosis by regulating FOXO and GADD34 and further activate the NFκB and JAK/STAT signaling pathways to aggravate inflammation. Moreover, released inflammatory factors, such as iNOS, can activate autophagy through the AMPK and JNK signaling pathways. Mn also stimulates the PINK-1/Parkin protein by promoting the nuclear retention of FOXO3, inducing mitophagy (Section 4).