Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Abstract

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

Manganese-Induced Neurotoxicity through Impairment of Cross-Talk Pathways in Human Neuroblastoma Cell Line SH-SY5Y Differentiated with Retinoic Acid

“…Multiple genetic and environmental variables contribute to the onset and progression of Parkinson's disease, which is related with the degradation of DAergic neurons in the substantia nigra pars compacta [31]. Indeed, epidemiological studies have connected the development of neurodegeneration to Mn toxicity [22][23][24]51,52]. This can be mediated by impairment of protein metabolism, according to findings in nonhuman models [25,34,35].…”

“…These processes are potentially connected to 1522 diseases, of which 21 are associated with the nervous system [49]. Other functional and omics studies [25][26][27][28]34,35] have identified these potential mechanisms of Mn-induced neurotoxicity, reviewed by Tinkov et al [52]. In line with this, using microarray analysis and systems biology approaches, we verified a connection between Mn-induced acute cytotoxicity in the RA-differentiated SH-SY5Y-DAergic cell model and impairment of several pathways, including protein synthesis (18 processes), cell metabolism (10 processes), cell signaling (3 processes), neurodevelopment (1 process), and neurodegeneration (3 processes) (Tables 2 and 3).…”

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

“…Mn can interfere with the dopaminergic, cholinergic, glutamatergic, and GABAergic systems [78][79][80]. Mn disturbs these neurotransmitter systems through multiple mechanisms including the direct interaction with neurotransmitter receptors.…”

Gut Microbiota as a Potential Player in Mn-Induced Neurotoxicity

“…Mn also induces endoplasmic reticulum stress, which can lead to apoptosis and autophagy deregulation [37,38]; neuroinflammation, astrocytes being the main mediators of the proinflammatory effects of the metal [19,39]; alterations in cell signaling such as AKT, JNK, and other insulin-like pathways (this last one in Caenorhabditis elegans) [19,40,41]; and epigenetic alterations by increasing DNA methylation and histone acetylation in different models in vitro and in vivo [40][41][42]. Mn also interferes with GABAergic and catecholaminergic neurotransmissions by reducing the production of the neurotransmitters.…”

“…Several mechanisms by which Mn causes neurotoxicity have been unraveled, but it is still considered poorly understood. Multiple analyses of pathways affected by Mn exposure using metallomics, proteomics, gene expression, and bioinformatics revealed that Mn exposure alters several processes such as proteostasis, cell metabolism and signaling, immunity and inflammation, cell cycle, and neurodegeneration-associated pathways [ 19 ]. It is well established that Mn accumulates in areas rich in dopaminergic neurons.…”