Neurotoxicity mechanisms of manganese in the central nervous system

Abstract Chronic exposure to manganese (Mn) leads to a neurological disorder referred to as manganism, with pathological symptoms resembling those of Parkinson's disease (PD). However, the molecular mechanisms involved in Mn-induced neurotoxicity remain to be established. This review focuses on Mn-induced dysregulation of mitochondrial dynamics, mitophagy, autophagy, oxidative and nitrosative stress, inflammation, glutamate transporters and NMDA receptors, ultimately leading to neuronal death. The roles of astrocytes and microglia as key neural cell sources of Mn-induced neuroinflammation via NF-κB signaling and NLRP3 inflammasomes are also reviewed. In addition, we discuss Mn-induced expression of several genes that are associated with the aforementioned Mn-induced toxicity mechanisms, such as Yin Yang 1 (YY1) in glutamate transporters, repressor element 1 silencing transcription factor (REST) and nuclear factor erythroid 2-related factor 2 (NRF2) in oxidative stress, transcription factor EB (TFEB) and forkhead box O3 (FOXO3) in mitophagy/autophagy, and α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in autophagy. Further studies are needed to better understand the intricacy of mechanisms of Mn-induced neurotoxicity as to develop efficient and novel therapeutic interventions.