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Abstract Manganese (Mn) has recently come into the limelight as an important environmental risk factor for neurodegenerative disorders. Although multiple neurotoxicity of Mn have been extensively studied, the exact mechanism of Mn-induced autophagic dysregulation is still poorly understood. The main aim of this study was to explore the role of cytosolic high-mobility group box 1 (HMGB1)-dependent autophagy in Mn-induced autophagic dysregulation and neurotoxicity. SH-SY5Y cells were treated with culture solution (control) and three different concentrations of Mn (50, 100, and 200 μM) for 24 h to detect the effect of Mn on HMGB1-dependent autophagy. We found Mn could increase the HMGB1 mRNA level and its cytosolic translocation and dysregulate autophagy, and Mn-induced alpha-synuclein overexpression interfered with the interaction of HMGB1 and Beclin1, to subsequently promote Beclin1 binding to Bcl2. Another important finding was the neuroprotective role of corynoxine B (Cory B) in Mn-induced autophagic dysregulation and neurotoxicity. We set up six experimental groups: control (culture solution); 200 μM Mn treatment; 100 μM Cory B-alone treatment; and three different pretreated concentrations of Cory B (25, 50, and 100 μM). Our results showed that Cory B ameliorated Mn-induced autophagic dysregulation and neurotoxicity partly by dissociating HMGB1 from alpha-synuclein and inhibiting mTOR signaling. Highlights • Mn-induced autophagy is related to HMGB1-Beclin1 binding. • Mn-induced α-SYN protein disturbs HMGB1-dependent autophagy. • Cory B dissociates HMGB1 from α-SYN to bind to Beclin1. • Cory B ameliorates Mn-induced autophagic dysregulation and neurotoxicity. [ABSTRACT FROM AUTHOR]

Methylmercury (MeHg) is a environmental contaminant, which can induce neurotoxic effects. So far, the exact molecular mechanisms of autophagy and its effect on apoptosis in MeHg-induced neurotoxicity have not been elucidated. Here, rats were exposed to MeHg (4, 8, or 12 μmol/kg) for 4 weeks to evaluate the dose-effect relationship between MeHg and apoptosis, or autophagy in cerebral cortex. On this basis, rapamycin (Rapa) or 3-methyladenine (3-MA) was administrated to further explore the regulatory mechanisms of autophagy on MeHg-induced neuronal apoptosis. The pathological changes, autophagy or apoptosis levels, expression of autophagic or apoptotic-associated factors such as mTOR, S6K1, 4EBP1, Vps34, Beclin1, p62, LC3, Bcl-2/Bax, caspase, or MAPKs were investigated. Results showed that MeHg dose-dependently induced pathological changes in cerebral cortex, and the levels of autophagy and apoptosis were increased. Furthermore, Rapa pretreatment antagonized MeHg-induced apoptosis, whereas 3-MA further aggravated apoptosis, which were supported by findings that Rapa activated mTOR-mediated autophagy while 3-MA inhibited Vps34-related autophagy, further affect neuronal apoptosis through regulation of apoptotic factors mentioned above. In conclusion, the findings indicated that MeHg dose-dependently induced autophagy or apoptosis, and mTOR or Vps34 may play important roles in mediating autophagy, which further regulated apoptosis through MAPKs or mitochondrial apoptosis pathways. [Display omitted] • MeHg could induce autophagy and apoptosis in cerebral cortex. • The mTOR and Vps34 are involved in autophagy regulation. • The mitochondrial pathway and MAPKs are involved in apoptosis regulation. • Inhibition of mTOR could induce autophagy and antagonize the apoptosis. • Inhibition of Vps34 could decrease autophagy and aggravate the apoptosis. [ABSTRACT FROM AUTHOR]