Alpha-Synuclein Regulates Neuronal Levels of Manganese and Calcium

Dučić, Tanja; Carboni, Eleonora; Lai, Barry; Chen, Si; Michalke, Bernhard; Lázaro, Diana F.; Outeiro, Tiago F.; Bähr, Mathias; Barski, Elisabeth; Lingor, Paul

doi:10.1021/acschemneuro.5b00093

Cited by 38 publications

(33 citation statements)

References 52 publications

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“…At the neuronal level, α-synuclein (α-Syn) is believed to contribute to Mn homeostasis in neurons (130). Overexpression of increased intracellular Mn levels, whereas levels of Ca, Zn, K, P, and S were significantly decreased with not altering the expression patterns of DMT1, voltage-gated Ca-channels and ferroportin.…”

Section: Mn Influx: Tfr Dmt1 Zip8/zip14 Calcium Channels Citrate mentioning

confidence: 99%

“…Overexpression of increased intracellular Mn levels, whereas levels of Ca, Zn, K, P, and S were significantly decreased with not altering the expression patterns of DMT1, voltage-gated Ca-channels and ferroportin. Thus, α-Syn may act as an intracellular Mn store and neurotoxicity associated with PD might be mediated via regulation of transition metal levels and the metal-binding capacity of α-Syn (130).…”

Section: Mn Influx: Tfr Dmt1 Zip8/zip14 Calcium Channels Citrate mentioning

confidence: 99%

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Manganese metabolism in humans

2018

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Manganese (Mn) is an essential nutrient for intracellular activities; it functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and Mn superoxide dismutase (Mn-SOD). Through these metalloproteins, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. Mn deficiency is rare. In contrast Mn poisoning may be encountered upon overexposure to this metal. Excessive Mn tends to accumulate in the liver, pancreas, bone, kidney and brain, with the latter being the major target of Mn intoxication. Hepatic cirrhosis, polycythemia, hypermanganesemia, dystonia and Parkinsonism-like symptoms have been reported in patients with Mn poisoning. In recent years, Mn has come to the forefront of environmental concerns due to its neurotoxicity. Molecular mechanisms of Mn toxicity include oxidative stress, mitochondrial dysfunction, protein misfolding, endoplasmic reticulum (ER) stress, autophagy dysregulation, apoptosis, and disruption of other metal homeostasis. The mechanisms of Mn homeostasis are not fully understood. Here, we will address recent progress in Mn absorption, distribution and elimination across different tissues, as well as the intracellular regulation of Mn homeostasis in cells. We will conclude with recommendations for future research areas on Mn metabolism.

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Section: Mn Influx: Tfr Dmt1 Zip8/zip14 Calcium Channels Citrate mentioning

confidence: 99%

Section: Mn Influx: Tfr Dmt1 Zip8/zip14 Calcium Channels Citrate mentioning

confidence: 99%

Manganese metabolism in humans

2018

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“…In C. elegans , α-Syn attenuates Mn-induced toxicity in the background of PD-associated genes [126]. Recently, α-Syn has been proposed to act as a intracellular Mn store [127]. …”

Section: Main Textmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Peres

Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

294

183

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Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

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“…A similar perinuclear accumulation is observed in other cell systems. Recently, SXRF imaging of mouse pancreatic beta cells, mouse primary dopaminergic and hippocampal neurons, have also evidenced the perinuclear localization of Mn which might potentially be located within the Golgi apparatus although in these studies a correlative microscopy approach was not implemented (35)(36)(37)(38). For instance (35) reported that in the MIN6 mouse pancreatic beta cell line, Mn was prevalent in the cytoplasm and localized primarily in a perinuclear region, and hypothesized that this localization could possibly correspond to the Golgi apparatus.…”

Section: Mn Accumulates In the Golgi Apparatus Of Cells Not Expressinmentioning

confidence: 99%

SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus

Carmona

Zogzas

Roudeau

et al. 2018

ACS Chem. Neurosci.

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Manganese (Mn) is an essential metal that can be neurotoxic when elevated exposition occurs leading to parkinsonian-like syndromes. Mutations in the Slc30a10 gene have been identified in new forms of familial parkinsonism. SLC30A10 is a cell surface protein involved in the efflux of Mn protecting the cell against Mn toxicity. Disease causing mutations block the efflux activity of SLC30A10, resulting in Mn accumulation. Determining the intracellular localization of Mn when disease-causing SLC30A10 mutants are expressed is essential to elucidate the mechanisms of Mn neurotoxicity. Here, using organelle fluorescence microscopy and synchrotron X-ray fluorescence (SXRF) imaging we found that Mn accumulates in the Golgi apparatus of human cells transfected with the disease-causing SLC30A10-Δ105-107 mutant under physiological conditions and after exposure to Mn. In cells expressing the wild-type SLC30A10 protein, cellular Mn content was low after all exposure conditions, confirming efficient Mn efflux. In non-transfected cells that do not express endogenous SLC30A10, and in mock transfected cells, Mn was located in the Golgi apparatus, similarly to its distribution in cells expressing the mutant protein, confirming deficient Mn efflux. The newly developed SXRF cryogenic nano-imaging (<50 nm resolution) indicated that Mn was trapped in single vesicles within the Golgi apparatus. Our results confirm the role of SLC30A10 in Mn efflux and the accumulation of Mn in cells expressing the disease causing SLC30A10-Δ105-107 mutation. Moreover, we identified sub-organelle Golgi nano-vesicles as the main compartment of Mn accumulation in SLC30A10 mutants suggesting interactions with the vesicular trafficking machinery as a cause of the disease.

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Alpha-Synuclein Regulates Neuronal Levels of Manganese and Calcium

Cited by 38 publications

References 52 publications

Manganese metabolism in humans

Manganese metabolism in humans

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus

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