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Accueil du site > ANGLAIS > Research > CIS - Chemical Imaging and Speciation > Research projects > Manganese in parkinsonism


Manganese in parkinsonism

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Manganese (Mn) is an essential metal but it is neurotoxic at high dose, leading to parkinsonism, a clinical syndrome with symptoms of Parkinson’s disease. We studied this toxicity in the case of a familial mutation affecting the Mn transporter SLC30A10. This protein is normally responsible for the efflux of Mn and protects the cell against the toxicity of this metal.
Using organelle fluorescence optical microscopy and synchrotron X-ray fluorescence imaging, we found that Mn accumulates in the Golgi apparatus of cells expressing the disease-causing mutation SLC30A10-Δ105–107. These first results of the distribution of Mn in cells affected by the mutation were obtained at the DESY synchrotron (Hamburg, Germany). The distribution maps were completed with new images obtained at ESRF synchrotron (The European synchrotron, Grenoble) in order to specify the precise location of Mn in cells: the Mn is trapped in nano-vesicules (50nm) within the Golgi apparatus. These results suggest that the disease is caused by the accumulation of Mn in the Golgi apparatus that interferes with the vesicular trafficking machinery.

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Figure 1. Potassium (K) and manganese (Mn) distributions in cell expressing the SLC30A10-Δ105–107 mutant protein. The mutation blocks the efflux, leading to an accumulation of Mn in cells. It accumulates in very small vesicules, as small as the beam size of the synchrotron beam (50 nm). These distribution maps were obtained by synchrotron X-ray fluorescence imaging on the ESRF ID16A beamline.

Collaborations

Institute for Cellular and Molecular Biology and Institute for Neuroscience, University of Texas at Austin, USA

P06 Hard X-ray microprobe P06 Beamline (DESY), Hamburg

ID16A Nano-imaging beamline, ESRF (The European Synchrotron), Grenoble.

Reference

SLC30A10 mutation involved in parkinsonism results in manganese accumulation within nano-vesicles of the Golgi apparatus
Carmona A., Zogzas C.E., Roudeau S., Porcaro F., Garrevoet J., Spiers K., Salome M., Cloetens P., Mukhopadhyay S., Ortega R. (2019), ACS Chem Neurosci., 10, 1, 599-609. [pubmed] [link]

These results complete and confirm our previous work about Mn distribution in cells after exposure to environmental compounds. Organometallic manganese compounds are used as pesticides (Maneb), or as additives in unleaded gasoline (MMT).

Using micro-SXRF methods (Synchrotron X -Ray Fluorescence) and micro-XAS (X -ray Absorption Spectroscopy) at the ESRF (European Synchrotron Radiation Facility), we highlighted the accumulation of manganese in the Golgi apparatus of dopaminergic cells (Figure 2).

This result, completely new, tells us about the detoxification mechanisms of this element and the possible link to parkinsoninian syndromes. Disruption of vesicular trafficking by alteration and fragmentation of the Golgi apparatus could explain the neurotoxic effects of Mn, especially on the critical dopaminergic system affected by neurodegeneration.

In addition we have shown that whatever the nature of environmental Mn compounds (inorganic, organometallic), the mechanism of toxicity is the same and involves an interaction of Mn2+ ions with the Golgi apparatus. Toxicity is proportional to the solubility of the compounds, as shown by speciation, joining the toxicity paradigm vs solubility described for cobalt oxide.

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Figure 2. Micro-SXRF imaging and micro-XAS spectroscopy of dopaminergic neurons exposed in vitro to Mn showing accumulation in the Golgi apparatus and speciation as Mn2+. Data obtained at the ESRF ID21 beamline. Scale bar : 10 µm.

Environmental manganese compounds accumulate as Mn(II) within the Golgi apparatus of dopamine cells : relationship between speciation, subcellular distribution, and cytotoxicity
Carmona A., Roudeau S., Perrin L., Veronesi G., Ortega R. (2014), Metallomics, 6, 822-832. [pubmed] [link]

Manganese accumulates within Golgi apparatus in dopaminergic cells as revealed by synchrotron X-Ray fluorescence nano-imaging
Carmona A., Devès G., Roudeau S., Cloetens P., Bohic S., Ortega R. (2010), ACS Chemical Neurosciences, 1, 194-203.[pubmed] [link]