Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function

Abstract

Environmental exposure to neurotoxic metals and metalloids such as arsenic, cadmium, lead, mercury, or manganese is a global health concern affecting millions of people worldwide. Depending on the period of exposure over a lifetime, environmental metals can alter neurodevelopment, neurobehavior, and cognition and cause neurodegeneration. There is increasing evidence linking environmental exposure to metal contaminants to the etiology of neurological diseases in early life (e.g., autism spectrum disorder) or late life (e.g., Alzheimer's disease). The known main molecular mechanisms of metal-induced toxicity in cells are the generation of reactive oxygen species, the interaction with sulfhydryl chemical groups in proteins (e.g., cysteine), and the competition of toxic metals with binding sites of essential metals (e.g., Fe, Cu, Zn). In neurons, these molecular interactions can alter the functions of neurotransmitter receptors, the cytoskeleton and scaffolding synaptic proteins, thereby disrupting synaptic structure and function. Loss of synaptic connectivity may precede more drastic alterations such as neurodegeneration. In this article, we will review the molecular mechanisms of metal-induced synaptic neurotoxicity.

Keywords: arsenic; cadmium; lead; manganese; mercury; metal; neurotoxicity; synapse.

Figure 1

Interaction sites of environmental metal toxicants with the NMDA receptor. Cd²⁺ neuronal uptake is mediated by the NMDAR following its stimulation. Similarly, Mn²⁺ can permeate the plasma membrane through the NMDAR. Cd can bind directly to the DRPEER sequence in the extracellular domain (in the ABD/TMD linker) of the GluN1 subunit and inhibit NMDA-mediated current. Pb competes with zinc to the zinc-binding site of the GluN2 subunit and alters the receptor function. In the case of Hg, there are some indications for interactions with the cysteine -SH groups involved in the control of NMDAR activity, although this suggestion still needs experimental evidence. In most cases, metals could induce ROS that would interact with the –SH groups of the NMDAR. Structure of the GluN1/2B NMDAR (Protein Data Bank accession 4PE5 [32]). Figure inspired from Hansen et al. [52].

Figure 2

Schematic representation of synaptic toxicity mechanisms by direct competition of toxic metals (M) with physiological metal binding sites (Cu, Zn) within cytoskeletal proteins (e.g., tubulin, F-actin and/or F-actin binding proteins), PSD scaffold proteins (e.g., SHANK), and neurotransmitter receptors (e.g., NMDAR). These metal–protein interactions can damage the synaptic structure and lead to loss of connectivity between neurons.