High levels of Mn²⁺ inhibit secretory pathway Ca²⁺/Mn²⁺‐ATPase (SPCA) activity and cause Golgi fragmentation in neurons and glia

Abstract

Manganese, which is found in cells mostly as Mn 2+, is an essential trace element for mammals which acts as a cofactor for a number of enzymes. It is crucial for brain development and metabolism, but in excess can be neurotoxic. Although alimentary exposure to high manganese is usually not the problem, parenteral uptake of this element represents the main route for manganese intoxication. Indeed, chronic Mn 2+ inhalation by occupational or environmental exposition (Nelson et al. 1993;Sierra et al. 1995) or increase of Mn 2+ concentration by long-lasting total parenteral nutrition (Ono et al. 1995) or in cirrhotic patients (Krieger et al. 1995;Tuschl et al. 2008) results in Mn 2+ deposition in brain, that can be detected as increased signal on T 1 -weighted magnetic resonance imaging mainly in the globus pallidus (Silva et al. 2004;Massaad and Pautler 2011). In view of its abundance in the environment and since Mn 2+ can passively enter the cells in an unspecific way via a multitude of other bivalent ion channels and carriers, cells seldom experience a shortage of Mn 2+ . The problem that cells face is rather to remove the ion from the cells. Mn 2+ can enter the brain via the blood capillaries and/or the cerebrospinal fluid, and its accumulation produces a severe and debilitating neurological disorder known as manganism (Olanow 2004). A generalized bradykinesia and widespread rigidity, with among other symptoms basal ganglia disturbances, make manganism resemble Parkinson′s disease (Calne et al. 1994). Cellular mechanisms Received January 18, 2012; revised manuscript received June 19, 2012; accepted July 18, 2012. Address correspondence and reprint requests to Ana M. Mata, Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06006 Badajoz, Spain. E-mail: anam@unex.esAbbreviations used: DAPI, 4′,6-diamidino-2-phenylindole; DMSO, dimethyl sulphoxide; EDTA, ethylenediamine-tetraacetic acid; ER, endoplasmic reticulum; MTT, 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PVDF, polyvinylidene difluoride; SPCA, secretory pathway Ca 2+ -ATPase; TBS, Tris-buffered saline. 824Journal | 2012 | 123 | 824-836 doi: 10.1111/j.1471-4159.2012.07888.x of Mn 2+ toxicity in brain are poorly understood, but seem to involve damage in different cellular types. Besides neurons acting as major functional elements in the brain, also the more numerous glial cells, which provide support for the neurons, are vulnerable to toxicity. In this study, we have prepared mouse primary cultures of neurons and glia to address the cellular impact of high extracellular Mn 2+ concentration. We examined cell morphology and focused in particular on the Golgi apparatus, an organelle particularly affected in neurodegenerative diseases (Gonatas et al. 2006). Furthermore, the Golgi houses the Ca 2+ /Mn 2+ -ATPases of the secretory pathway (SPCAs), a group of ion-motive ATPases with two isoforms, SPCA1 and -2, identified in higher vertebrates (reviewed...

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More than just sugars: Conserved oligomeric Golgi complex deficiency causes glycosylation‐independent cellular defects

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Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders

“…As such, SPCA1 might be implicated in the removal of toxic Mn 2+ from neurons through the secretory pathway (Vangheluwe et al, 2009). However, SPCA expression levels decrease with Mn 2+ -exposure and SPCA activity is inhibited by high concentrations of Mn 2+ , suggesting that other Mn 2+ -removal mechanisms may prevail in neurons (Sepulveda et al, 2012). …”