Mechanisms of Manganese Neurotoxicity

PROJECT SUMMARY Our understanding of how chronic Mn may trigger or promote central nervous system (CNS) morbidities remains fragmentary. Here, we seek to continue our studies into the mechanisms of Mn neurotoxicity by focusing on chronic exposures. Acute Mn cellular neurotoxicity occurs by alterations in cell signaling pathways that normally rely on Mn for their function, e.g., insulin-like growth factor (IGF)/insulin metabolic signaling pathway (IIS), and the highly interconnected mTOR (mTORC1 and mTORC2), AKT and ATM/p53 metabolic signaling systems. Existing research strongly supports a mechanism of Mn neurotoxicity related to the fact that Mn-dependent enzymes are situated at key regulatory nodes in these metabolic signaling pathways. New data support role for two other signaling systems linked to healthy aging in chronic Mn neurotoxicity, the eIF2 and Sirtuin (SIRT) signaling pathways. It is noteworthy that real-life Mn exposures in the human population occur over an extended period, months to years, involving lower extracellular or intracellular levels of Mn not associated with cell death in acute neurotoxicity studies. Mechanistic details underlying the biological changes that occur under chronic Mn intoxication remain elusive and thus warrant further investigation. Moreover, it is highly likely that persistent Mn effects are in a complex interplay with genetics, sex and age. Therefore, we seek to test the overarching hypothesis that chronic Mn neurotoxicity is caused by long-term elevated Mn altering the activity of neuronal cell signaling systems for which Mn normally acts as an essential co-factor that regulate healthy aging. To address this overarching hypothesis we have designed three highly meritorious Specific Aims, namely (1) determine the evolution of genetic pathways altered as Mn exposure extends from acute to chronic, and whether any such effects are persistent after cessation of chronic Mn overload, (2) evaluate the concurrent and persistent functional consequences of acute versus chronic Mn exposures and the influence of neural cell type, neurotransmitter- type, and genetic sex on the magnitude versus types of genetic pathways and functional outcomes altered, and (3) Explore the mechanistic basis of chronic/persistent Mn neurotoxicity phenotypes via metabolic analysis, with pharmacological and genetic manipulation of signaling and metabolic pathways in C. elegans and hiPSC neural model systems. Our highly interactive experimental design brings to bear innovative and complementary expertise to assess shared genetic networks and functional outcomes of Mn-induced chronic neurotoxicity with translation from C. elegans to humans.