Alpha-Synuclein Regulates Neuronal Levels of Manganese and Calcium.
Manganese (Mn) may foster aggregation of alpha-synuclein (αSyn) contributing to the pathogenesis of PD. Here, we examined the influence of αSyn overexpression on distribution and oxidation states of Mn in frozen-hydrated primary midbrain neurons (PMNs) by synchrotron-based X-ray fluorescence (XRF) and X-ray absorption near edge structure spectroscopy (XANES). Overexpression of αSyn increased intracellular Mn levels, whereas levels of Ca, Zn, K, P, and S were significantly decreased. Mn oxidation states were not altered. A strong correlation between Cu-/Mn-levels as well as Fe-/Mn-levels was observed in αSyn-overexpressing cells. Subcellular resolution revealed a punctate or filament-like perinuclear and neuritic distribution of Mn, which resembled the expression of DMT1 and MnSOD. While overexpression of αSyn did not significantly alter the expression patterns of the most-expressed Mn transport proteins (DMT1, VGCC, Fpn1), it attenuated the Mn release from Mn-treated neurons. Thus, these data suggest that αSyn may act as an intracellular Mn store. In total, neurotoxicity in PD could be mediated via regulation of transition metal levels and the metal-binding capacity of αSyn, which could represent a promising therapeutic target for this neurodegenerative disorder.
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Tanja
T
Dučić
Department of Neurology, University Medicine Göttingen , Robert-Koch-Str. 40, 37075 Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, 37073 Göttingen, Germany.
Eleonora
E
Carboni
Advanced Photon Source, Argonne National Laboratory , 9700 S. Cass Avenue, Argonne, Illinois 60439, United States .
Barry
B
Lai
Advanced Photon Source, Argonne National Laboratory , 9700 S. Cass Avenue, Argonne, Illinois 60439, United States .
Si
S
Chen
Helmholtz Zentrum München , Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Bernhard
B
Michalke
Department of Neurodegeneration and Restorative Research, University Medicine Göttingen , Waldweg 33, 37073 Göttingen, Germany.
Diana F
DF
Lázaro
Department of Neurodegeneration and Restorative Research, University Medicine Göttingen , Waldweg 33, 37073 Göttingen, Germany.
Tiago F
TF
Outeiro
Department of Neurology, University Medicine Göttingen , Robert-Koch-Str. 40, 37075 Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, 37073 Göttingen, Germany.
Mathias
M
Bähr
Department of Neurology, University Medicine Göttingen , Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Elisabeth
E
Barski
Department of Neurology, University Medicine Göttingen , Robert-Koch-Str. 40, 37075 Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, 37073 Göttingen, Germany.
Paul
P
Lingor
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008345:Manganese / Q000378:metabolism* / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013223:Statistics as Topic; D014162:Transfection; D056928:X-Ray Absorption Spectroscopy; D055114:X-Ray Microtomography; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D008345:Manganese; D002118:Calcium
X-ray fluorescence; XANES spectroscopy; alpha-synuclein; calcium; manganese