Division of Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Department of Molecular Pharmacology, Albert Einstein College of Medicine Bronx, New York, NY 10461, USA.
Molecules. 2020 Dec 12;25(24):5880. doi: 10.3390/molecules25245880.
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.
锰（Mn）是一种必需的微量元素，作为几种关键酶的辅助因子，如谷氨酰胺合成酶、精氨酸酶、丙酮酸脱羧酶和线粒体超氧化物歧化酶。然而，其慢性过度暴露会导致一种被称为锰中毒的神经障碍，表现出与帕金森病固有症状相似的症状。Mn 诱导毒性的病理症状是众所周知的，但 Mn 向大脑运输和导致 Mn 神经毒性的细胞毒性的潜在机制尚不完全清楚。大脑中的 Mn 水平由负责其摄取和外排的多种转运体调节，因此，这些转运体的失调可能导致 Mn 在大脑中的积累，从而引起神经毒性。它在大脑中的分布和亚细胞定位以及相关的亚细胞毒性机制也得到了广泛的研究。本综述强调了目前已知的 Mn 转运体及其在 Mn 诱导的神经毒性中的作用，以及其细胞内摄取后随后发生的分子和细胞失调，如氧化应激、神经炎症、神经传递中断、α-突触核蛋白聚集和淀粉样变性。
