Role of Astrocytes in Manganese Neurotoxicity Revisited

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2019 Oct 2

PMID 31571097

Citations 17

Authors

Tao Ke

Marta Sidoryk-Wegrzynowicz

Edward Pajarillo

Asha Rizor

Felix Alexandre Antunes Soares

Eunsook Lee

Michael Aschner

Affiliations

Soon will be listed here.

Abstract

Manganese (Mn) overexposure is a public health concern due to its widespread industrial usage and the risk for environmental contamination. The clinical symptoms of Mn neurotoxicity, or manganism, share several pathological features of Parkinson's disease (PD). Biologically, Mn is an essential trace element, and Mn in the brain is preferentially localized in astrocytes. This review summarizes the role of astrocytes in Mn-induced neurotoxicity, specifically on the role of neurotransmitter recycling, neuroinflammation, and genetics. Mn overexposure can dysregulate astrocytic cycling of glutamine (Gln) and glutamate (Glu), which is the basis for Mn-induced excitotoxic neuronal injury. In addition, reactive astrocytes are important mediators of Mn-induced neuronal damage by potentiating neuroinflammation. Genetic studies, including those with Caenorhabditis elegans (C. elegans) have uncovered several genes associated with Mn neurotoxicity. Though we have yet to fully understand the role of astrocytes in the pathologic changes characteristic of manganism, significant strides have been made over the last two decades in deciphering the role of astrocytes in Mn-induced neurotoxicity and neurodegeneration.

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References

Jentsch S, Schlenker S . Selective protein degradation: a journey's end within the proteasome. Cell. 1995; 82(6):881-4. DOI: 10.1016/0092-8674(95)90021-7. View

Chen P, DeWitt M, Bornhorst J, Soares F, Mukhopadhyay S, Bowman A . Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson's disease. Metallomics. 2014; 7(2):289-98. PMC: 4479152. DOI: 10.1039/c4mt00292j. View

Sillence D . New insights into glycosphingolipid functions--storage, lipid rafts, and translocators. Int Rev Cytol. 2007; 262:151-89. DOI: 10.1016/S0074-7696(07)62003-8. View

Lee E, Yin Z, Sidoryk-Wegrzynowicz M, Jiang H, Aschner M . 15-Deoxy-Δ12,14-prostaglandin J₂ modulates manganese-induced activation of the NF-κB, Nrf2, and PI3K pathways in astrocytes. Free Radic Biol Med. 2012; 52(6):1067-74. PMC: 3439999. DOI: 10.1016/j.freeradbiomed.2011.12.016. View

Karki P, Webb A, Smith K, Johnson Jr J, Lee K, Son D . Yin Yang 1 is a repressor of glutamate transporter EAAT2, and it mediates manganese-induced decrease of EAAT2 expression in astrocytes. Mol Cell Biol. 2014; 34(7):1280-9. PMC: 3993574. DOI: 10.1128/MCB.01176-13. View

Bjorklund G, Chartrand M, Aaseth J . Manganese exposure and neurotoxic effects in children. Environ Res. 2017; 155:380-384. DOI: 10.1016/j.envres.2017.03.003. View

Aschner M, Lukey B, Tremblay A . The Manganese Health Research Program (MHRP): status report and future research needs and directions. Neurotoxicology. 2005; 27(5):733-6. DOI: 10.1016/j.neuro.2005.10.005. View

Yan B, Gong C, Song J, Krausz T, Tretiakova M, Hyjek E . Arginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms. Am J Surg Pathol. 2010; 34(8):1147-54. PMC: 3160135. DOI: 10.1097/PAS.0b013e3181e5dffa. View

Pawlik T, Souba W, Sweeney T, Bode B . Phorbol esters rapidly attenuate glutamine uptake and growth in human colon carcinoma cells. J Surg Res. 2000; 90(2):149-55. DOI: 10.1006/jsre.2000.5872. View

10.

Hudnell H . Effects from environmental Mn exposures: a review of the evidence from non-occupational exposure studies. Neurotoxicology. 1999; 20(2-3):379-97. View

11.

Fang T, Al Khleifat A, Meurgey J, Jones A, Leigh P, Bensimon G . Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018; 17(5):416-422. PMC: 5899963. DOI: 10.1016/S1474-4422(18)30054-1. View

12.

Deitmer J, Broer A, Broer S . Glutamine efflux from astrocytes is mediated by multiple pathways. J Neurochem. 2003; 87(1):127-35. DOI: 10.1046/j.1471-4159.2003.01981.x. View

13.

Oliver C . Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys. 1989; 275(2):559-67. DOI: 10.1016/0003-9861(89)90402-5. View

14.

Milanese M, Giribaldi F, Melone M, Bonifacino T, Musante I, Carminati E . Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2013; 64:48-59. DOI: 10.1016/j.nbd.2013.11.006. View

15.

Aschner M, Gannon M, Kimelberg H . Manganese uptake and efflux in cultured rat astrocytes. J Neurochem. 1992; 58(2):730-5. DOI: 10.1111/j.1471-4159.1992.tb09778.x. View

16.

Yuan S, Zhang Z, Li Z . Cell Death-Autophagy Loop and Glutamate-Glutamine Cycle in Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2017; 10:231. PMC: 5519524. DOI: 10.3389/fnmol.2017.00231. View

17.

Aschner J, Anderson A, Slaughter J, Aschner M, Steele S, Beller A . Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition. Am J Clin Nutr. 2015; 102(6):1482-9. PMC: 4658463. DOI: 10.3945/ajcn.115.116285. View

18.

Popichak K, Afzali M, Kirkley K, Tjalkens R . Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese. J Neuroinflammation. 2018; 15(1):324. PMC: 6247759. DOI: 10.1186/s12974-018-1349-4. View

19.

Erikson K, Dorman D, Lash L, Aschner M . Duration of airborne-manganese exposure in rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity. Neurotoxicology. 2008; 29(3):377-85. DOI: 10.1016/j.neuro.2007.12.007. View

20.

Barhoumi R, Faske J, Liu X, Tjalkens R . Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma cells through mitochondrial-dependent activation of nuclear factor kappaB. Brain Res Mol Brain Res. 2004; 122(2):167-79. DOI: 10.1016/j.molbrainres.2003.12.009. View