alpha-synuclein and Manganese-Poisoning

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.

Topics: alpha-Synuclein; Animals; Brain; Calcium Channels; Carrier Proteins; Cation Transport Proteins; Humans; Inflammation; Manganese; Manganese Poisoning; Neurotoxins; Neurotransmitter Agents; Oxidative Stress; Transcription Factors; Transferrin

Manganism is a distinct medical condition from Parkinson's disease. Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels. Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the globus pallidus to the entire area of the basal ganglia, including the substantia nigra pars compacta involved in Parkinson's disease. The mechanisms of manganese neurotoxicity from chronic exposure to very low levels are not well understood, but promising information is based on the concept of susceptibility that may place individuals exposed to manganese at a higher risk for developing Parkinsonian disturbances. These conditions include mutations of genes which play important pathogenetic roles in both Parkinsonism and in the regulation of manganese transport and metabolism. Liver function is also important in manganese-related neurotoxicity and sub-clinical impairment may increase the risk of Parkinsonism. The purpose and scope of this report are to explore the literature concerning manganese exposure and potential subclinical effects and biological pathways, impairment, and development of diseases such as Parkinsonism and manganism. Inhalation and ingestion of manganese will be the focus of this report.

Topics: alpha-Synuclein; Basal Ganglia; Environmental Exposure; Globus Pallidus; Humans; Male; Manganese; Manganese Poisoning; Occupational Exposure; Parkinson Disease, Secondary; Proton-Translocating ATPases; Substantia Nigra; Ubiquitin-Protein Ligases; Welding; Workforce

Manganese (Mn) is an environmental pollutant having a toxic effect on Parkinson's disease, with significant damage seen in the neurons of basal ganglia. Hence, Mn pollution is a public health concern. A Sprague-Dawley rat model was used to determine the damage to basal nuclei, and the effect of Mn intake was detected using the Morris water maze test and transmission electron microscopy. The SH-SY5Y cell line was exposed to Mn, and downstream signaling was assessed to determine the mechanism of toxicity. Mn exposure injured neurons, repressing GABA

Topics: alpha-Synuclein; Animals; Basal Ganglia; Cyclic AMP Response Element-Binding Protein; KATP Channels; Male; Manganese Poisoning; Maze Learning; Memory Disorders; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Receptors, GABA; Receptors, GABA-A; Receptors, GABA-B

The pathological role of α-synuclein (α-Syn) aggregation in neurodegeneration is well recognized, but the physiological function of normal α-Syn remains unknown. As α-Syn protein contains multiple divalent metal binding sites, herein we conducted a comprehensive characterization of the role of α-Syn in manganese-induced dopaminergic neurotoxicity. We established transgenic N27 dopaminergic neuronal cells by stably expressing human wild-type α-Syn at normal physiological levels. α-Syn-expressing dopaminergic cells significantly attenuated Mn-induced neurotoxicity for 24-h exposures relative to vector control cells. To further explore cellular mechanisms, we studied the mitochondria-dependent apoptotic pathway. Analysis of a key mitochondrial apoptotic initiator, cytochrome c, revealed that α-Syn significantly reduces the Mn-induced cytochrome c release into cytosol. The downstream caspase cascade, involving caspase-9 and caspase-3 activation, during Mn exposure was also largely attenuated in Mn-treated α-Syn cells in a time-dependent manner. α-Syn cells also showed a dramatic reduction in the Mn-induced proteolytic activation of the pro-apoptotic kinase PKCδ. The generation of Mn-induced reactive oxygen species (ROS) did not differ between α-Syn and vector control cells, indicating that α-Syn exerts its protective effect independent of altering ROS generation. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed no significant differences in intracellular Mn levels between treated vector and α-Syn cells. Notably, the expression of wild-type α-Syn in primary mesencephalic cells also rescued cells from Mn-induced neurotoxicity. However, prolonged exposure to Mn promoted protein aggregation in α-Syn-expressing cells. Collectively, these results demonstrate that wild-type α-Syn exhibits neuroprotective effects against Mn-induced neurotoxicity during the early stages of exposure in a dopaminergic neuronal model of PD.

Topics: alpha-Synuclein; Animals; Apoptosis; Binding Sites; Blotting, Western; Cell Culture Techniques; Cell Line; Cell Survival; Chlorides; DNA Fragmentation; Dopamine; Dopaminergic Neurons; Humans; Manganese Compounds; Manganese Poisoning; Mesencephalon; Models, Neurological; Parkinson Disease; Protein Binding; Rats; Reactive Oxygen Species; Spectrophotometry, Atomic; Transfection

Overexposure to manganese (Mn) has been known to induce neuronal damage. However, little is known of the role that reactive oxygen species (ROS) play in protein aggregation resulting from Mn exposure. The current study investigated whether oxidative stress is involved in manganese-induced alpha-synuclein oligomerization in organotypic brain slices. After application of Mn (0-400μM) for 24h, there was a dose-dependent increase in average percentage of propidium iodide positive (PI(+)) nuclei in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, the treatment with Mn resulted in a dose-dependent increase in neurocyte apoptosis, ROS level, and decrease in superoxide dismutase (SOD) activity. Mn also caused oxidative damage in cell lipid and protein. At the same time, the exposure of Mn leaded to significantly increase in the expression of alpha-synuclein mRNA and protein. Alpha-synuclein oligomerization occurred in Mn-treated slices, especially on membrane-bound form. It indicated that alpha-synuclein oligomers were more likely to combination cell membranes and resulting in membrane damage. Mn-induced neurocyte damage and alpha-synuclein oligomerization were also partially alleviated by the pretreatment with GSH and aggravated by H2O2 pretreatment. The findings revealed Mn might exert its neurotoxic effects by oxidative stress-mediated alpha-synuclein oligomerization in organotypic brain slices.

Topics: alpha-Synuclein; Animals; Apoptosis; Basal Ganglia; Blotting, Western; Brain; Brain Chemistry; Glutathione; Hydrogen Peroxide; L-Lactate Dehydrogenase; Manganese; Manganese Poisoning; Neurons; Organ Culture Techniques; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; RNA; Sulfhydryl Compounds; Superoxide Dismutase