Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

Abstract

Chronic exposure to elevated levels of manganese via occupational or environmental settings causes a neurological disorder known as manganism, resembling the symptoms of Parkinson’s disease, such as motor deficits and cognitive impairment. Numerous studies have been conducted to characterize manganese’s neurotoxicity mechanisms in search of effective therapeutics, including natural and synthetic compounds to treat manganese toxicity. Several potential molecular targets of manganese toxicity at the epigenetic and transcriptional levels have been identified recently, which may contribute to develop more precise and effective gene therapies. This review updates findings on manganese-induced neurotoxicity mechanisms on intracellular insults such as oxidative stress, inflammation, excitotoxicity, and mitophagy, as well as transcriptional dysregulations involving Yin Yang 1, RE1-silencing transcription factor, transcription factor EB, and nuclear factor erythroid 2-related factor 2 that could be targets of manganese neurotoxicity therapies. This review also features intracellular proteins such as PTEN-inducible kinase 1, parkin, sirtuins, leucine-rich repeat kinase 2, and α-synuclein, which are associated with manganese-induced dysregulation of autophagy/mitophagy. In addition, newer therapeutic approaches to treat manganese’s neurotoxicity including natural and synthetic compounds modulating excitotoxicity, autophagy, and mitophagy, were reviewed. Taken together, in-depth mechanistic knowledge accompanied by advances in gene and drug delivery strategies will make significant progress in the development of reliable therapeutic interventions against manganese-induced neurotoxicity.

Dose–response relationship between multiple trace elements and risk of all-cause mortality: a prospective cohort study

“…However, studies on the association of these trace elements with the risk of all-cause mortality are rare. Numerous studies have been carried out to describe the neurotoxic mechanisms of manganese ( 38 , 39 ). Further studies are needed to explore the association between the dose–response relationship of these trace elements in the body and the risk of all-cause mortality and other diseases.…”

Scientific opinion on the tolerable upper intake level for manganese

“…It is also suggested that manganese can impair the function of astrocytic glutamate transporters (glutamate transporter 1, GLT‐1 and glutamate aspartate transporter, GLAST) and glutamate uptake, leading to disruption of glutamate homeostasis and excitotoxic neuronal injury, eventually causing neurodegeneration (Fumagalli et al., 2008; Karki et al., 2015; Lee et al., 2009; Pajarillo et al., 2022).…”

“…Since one of the roles of astrocytes is regulation of immune responses with production of cytokines and inflammatory mediators, several studies have shown that dysregulation of mitochondrial bioenergetics in astrocytes may result in neuroinflammation, leading to neuronal injury (Kirkley et al., 2017; Pajarillo et al., 2022; Sarkar et al., 2018; Verina et al., 2011; Zhao et al., 2009).…”