Abstract
Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced α-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.
Highlights
Manganese (Mn) is an essential nutrient because it is required for cellular function in many metabolic pathways
brain-derived neurotrophic factor (BDNF) binding to tropomyosin kinase receptor B (TrkB) triggers its dimerization through conformational changes and autophosphorylation of tyrosine residues in its intracellular domain (ICD), activating mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C-g1 (PLC-γ1) signaling pathways, and mediating neural differentiation, survival, and neurogenesis[6]
We speculate that the overexpression of α-Syn and its subsequent interference with BDNF/TrkB signaling may play an important role in linking the complicated neurobehavioral deficiency observed following Mn exposure, the molecular mechanism of this process remains elusive
Summary
Manganese (Mn) is an essential nutrient because it is required for cellular function in many metabolic pathways. The central nervous system (CNS) is highly vulnerable to Mn toxicity, which leads to many sensory disturbances and neurobehavioral deficiency. Manganism is characterized by BDNF, acting through the receptor tropomyosin kinase receptor B (TrkB), is considered a key molecule in the Official journal of the Cell Death Differentiation Association. Kang[7] found that α-synuclein (α-Syn), when overexpressed, selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. Α-Syn localizes to presynaptic terminals nearby synaptic vesicles and is predominantly expressed in the neurons of the CNS. We speculate that the overexpression of α-Syn and its subsequent interference with BDNF/TrkB signaling may play an important role in linking the complicated neurobehavioral deficiency observed following Mn exposure, the molecular mechanism of this process remains elusive
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