Manganese Accumulation in the Brain via Various Transporters and Its Neurotoxicity Mechanisms

Abstract

Manganese (Mn) is an essential trace element, serving as a cofactor for several key enzymes, such as glutamine synthetase, arginase, pyruvate decarboxylase, and mitochondrial superoxide dismutase. However, its chronic overexposure can result in a neurological disorder referred to as manganism, presenting symptoms similar to those inherent to Parkinson’s disease. The pathological symptoms of Mn-induced toxicity are well-known, but the underlying mechanisms of Mn transport to the brain and cellular toxicity leading to Mn’s neurotoxicity are not completely understood. Mn’s levels in the brain are regulated by multiple transporters responsible for its uptake and efflux, and thus, dysregulation of these transporters may result in Mn accumulation in the brain, causing neurotoxicity. Its distribution and subcellular localization in the brain and associated subcellular toxicity mechanisms have also been extensively studied. This review highlights the presently known Mn transporters and their roles in Mn-induced neurotoxicity, as well as subsequent molecular and cellular dysregulation upon its intracellular uptakes, such as oxidative stress, neuroinflammation, disruption of neurotransmission, α-synuclein aggregation, and amyloidogenesis.

Multi-Elemental Analysis of Human Optic Chiasm—A New Perspective to Reveal the Pathomechanism of Nerve Fibers’ Degeneration

“…In addition, there is an association between elevated levels of certain metals and other neurological diseases such as Guillain–Barré disease (GBD), Gulf War Syndrome (GWS), Huntington’s disease (HD), manganism, multiple sclerosis, and Wilson’s disease (WD). Disturbed macro- and micro-element homeostasis has been observed in the brain of alcohol-dependent patients and even in those who died as a result of suicide [ 16 , 17 , 18 , 19 , 20 ].…”

Time course of pulmonary inflammation and trace element biodistribution during and after sub-acute inhalation exposure to copper oxide nanoparticles in a murine model

“…Mn in brain in our study was significantly elevated compared to controls. Mn induces oxidative stress and neuroinflammation and dysregulates multiple neurotransmitters associated with motor deficits, learning, memory and cognition [ 53 ] and thus inhalation of CuO NPs may cause neurotoxicity indirectly through disruption of trace element transporter which should be investigated further [ 54 ].…”

Sex‐dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure

“…54 Similarly, Mn accumulates in the hippocampus, cerebellum, 55,56 and cortex. 57,58 Although it well established that Mn deposition in the brain is region-specific owing to differential expression of important Mn transporters-DMT-1, transferrin, across specific brain regions, 59 sex-specific distribution and metabolism of Mn have also been recorded both in humans [60][61][62] and experimental models. 40,63 Similarly, we observed differences in Mn levels in male vs. female cortex, with elevated Mn levels in males and absent of significant change in females.…”