Manganese-Induced Neurotoxicity: New Insights Into the Triad of Protein Misfolding, Mitochondrial Impairment, and Neuroinflammation

Abstract

Occupational or environmental exposure to manganese (Mn) can lead to the development of "Manganism," a neurological condition showing certain motor symptoms similar to Parkinson's disease (PD). Like PD, Mn toxicity is seen in the central nervous system mainly affecting nigrostriatal neuronal circuitry and subsequent behavioral and motor impairments. Since the first report of Mn-induced toxicity in 1837, various experimental and epidemiological studies have been conducted to understand this disorder. While early investigations focused on the impact of high concentrations of Mn on the mitochondria and subsequent oxidative stress, current studies have attempted to elucidate the cellular and molecular pathways involved in Mn toxicity. In fact, recent reports suggest the involvement of Mn in the misfolding of proteins such as α-synuclein and amyloid, thus providing credence to the theory that environmental exposure to toxicants can either initiate or propagate neurodegenerative processes by interfering with disease-specific proteins. Besides manganism and PD, Mn has also been implicated in other neurological diseases such as Huntington's and prion diseases. While many reviews have focused on Mn homeostasis, the aim of this review is to concisely synthesize what we know about its effect primarily on the nervous system with respect to its role in protein misfolding, mitochondrial dysfunction, and consequently, neuroinflammation and neurodegeneration. Based on the current evidence, we propose a 'Mn Mechanistic Neurotoxic Triad' comprising (1) mitochondrial dysfunction and oxidative stress, (2) protein trafficking and misfolding, and (3) neuroinflammation.

Keywords: Parkinson’s disease; cell-to-cell transmission and neuroinflammation; exosome; manganese neurotoxicity; protein aggregation.

FIGURE 1

Receptors/Channels involved in Mn homeostasis. Various cellular receptors such as divalent metal transporter 1 (DMT1) and transferrin receptor (TfR), as well as ion channels, store-operated Ca⁺² channels (SOCC) or voltage-gated Ca⁺² channels (VGCC) that facilitate the entry of divalent Mn into cells, whereas SLC40A (ferroportin) and Ca⁺² facilitate its expulsion from cells and mitochondria, respectively. Mn⁺² is passively transported via VGCC and glutamate-activated ion channels while Mn⁺³ entry is facilitated via transferrin.

FIGURE 2

The structure of α-synuclein. (A) Orange boxes denote the characteristic KTKEGV repeat and red lines denote amino acid mutations seen in familial PD patients. The central hydrophobic core (middle light blue), or NAC domain, promotes α-synuclein aggregation. The C-terminal domain (right dark blue) is the acidic tail and contains most known phosphorylation sites. (B) Gray boxes denote known metal-binding sites in the α-synuclein structure.

FIGURE 3

Effect of chronic Mn overexposure on α-synuclein misfolding. Metal-binding sites on α-synuclein (αSyn) allow it to become a metal sink for free-roaming metals in cells. During an acute exposure to Mn, free-roaming Mn binds to the metal-binding sites on the C-terminus of this protein. In this way, αSyn effectively works as a chelator for different metal ions, including Mn. However, continued exposure to Mn can saturate this chelating property. Once saturation occurs following additional binding of Mn to the C-terminus, the natively conformed protein misfolds. Misfolded αSyn leads to the production of pro-inflammatory factors. Thus, Mn overexposure leads to progressive protein misfolding in the neurons and induces inflammation and finally neurodegeneration.

FIGURE 4

Mn-induced cell death: Cellular Mn homeostasis is dependent upon efficient uptake, retention and excretion by various cell receptors and/or ion channels. In the presence of excess Mn, homeostatic mechanisms will down-regulate the receptors involved in the uptake of this metal, while up-regulating those involved in its release from the cell. However, during chronic exposure to high concentrations of Mn, these system checks are not maintained. Continued uptake of Mn under these conditions increases the production of reactive oxygen species (ROS), leading to mitochondrial dysfunction. Impaired mitochondrial function leads to the release of cytochrome c, activating the apoptosis initiator caspase-9, which in turn cleaves caspase-3. The cleaved fragment of caspase-3 interacts with protein kinase C delta (PKCδ), a pro-apoptotic protein. Caspase-3-mediated proteolytic cleavage of PKCδ leads to DNA fragmentation and apoptosis.

FIGURE 5

Mn neurotoxic triad: by dysregulating key protein degradative and trafficking pathways, Mn overexposure results in a ‘neurotoxic triad’ comprising mitochondrial dysfunction and oxidative stress, protein misfolding and trafficking, and neuroinflammation.