Abstract
Manganese (Mn), an essential micronutrient, acts as a cofactor for multiple enzymes. Epidemiological investigations have shown that an excessive level of Mn is an important environmental factor involved in neurotoxicity. Frequent pollution of air and water by Mn is a serious threat to the health of the population. Overexposure to Mn is particularly detrimental to the central nervous system, leading to symptoms similar to several neurological disorders. Many different mechanisms have been implicated in Mn-induced neurotoxicity, including oxidative/nitrosative stress, toxic protein aggregation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, dysregulation of autophagy, and the apoptotic cascade, which together promote the progressive neurodegeneration of nerve cells. As a compensatory regulatory mechanism, autophagy plays dual roles in various biological activities under pathological stress conditions. Dysregulation of autophagy is involved in the development of neurodegenerative disorders, with recent emerging evidence indicating a strong, complex relationship between autophagy and Mn-induced neurotoxicity. This review discusses the connection between autophagy and Mn-induced neurotoxicity, especially alpha-synuclein oligomerization, ER stress, and aberrated protein S-nitrosylation, which will provide new insights to profoundly explore the precise mechanisms of Mn-induced neurotoxicity.
Highlights
MANGANESE AND NEUROTOXICITYManganese (Mn) is the fifth most abundant metal element overall on earth
Many different mechanisms have been implicated in Mn-induced neurotoxicity, including oxidative/nitrosative stress, toxic protein aggregation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, dysregulation of autophagy, and the apoptotic cascade, which together promote the progressive neurodegeneration of nerve cells
In SH-SY5Y cells, we found that the overexpressed α-syn induced by Mn preferentially binds to high mobility group protein B1 (HMGB1), disrupting Beclin1– HMGB1 autophagic induction, and exacerbating apoptosis via an increase of Beclin1–Bcl2 binding (Yan et al, 2019b)
Summary
Manganese (Mn) is the fifth most abundant metal element overall on earth It widely exists in ores, oxides, carbonates, and silicates (Horning et al, 2015). A proper level of Mn is crucial for human health, but excessive exposure to Mn may result in a neurotoxic disorder known as manganism (Horning et al, 2015; Parmalee and Aschner, 2016), which has symptoms resembling those of Parkinson’s disease (PD), involving the expression of cognitive, motor, and emotional deficits. Investigations of Mn overexposure over the past decade have mainly focused on oxidative/nitrosative stress, endoplasmic reticulum (ER) stress, energy failure, nerve cell apoptosis, mitochondrial dysregulation, alpha-synuclein (α-syn) oligomerization, alteration of neurotransmitter metabolism, and calcium dyshomeostasis (O’Neal and Zheng, 2015), while Mn deficiency is mostly due to the reduced activity of multiple Mn-dependent enzymes. Dysregulation of autophagy has been shown to contribute to Mn-induced apoptosis (Zhou et al, 2018; Zhang et al, 2019), but the molecular mechanisms underlying this neurotoxicity have yet to be fully elucidated
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