Journal
ACS CHEMICAL NEUROSCIENCE
Volume 6, Issue 10, Pages 1769-1779Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00093
Keywords
X-ray fluorescence; XANES spectroscopy; alpha-synuclein; manganese; calcium
Funding
- U.S. DOE [DE-AC02-06CH11357]
- Cluster of Excellence
- DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)
- Deutsche Akademische Auslandsdienst (DAAD)
- Else Kroner-Fresenius-Stiftung
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Manganese (Mn) may foster aggregation of alpha-synuclein (alpha Syn) contributing to the pathogenesis of PD. Here, we examined the influence of aSyn overexpression on distribution and oxidation states of Mn in frozen-hydrated primary midbrain neurons (PMNs) by synchrotron-based Xray fluorescence (XRF) and X-ray absorption near edge structure spectroscopy (XANES). Overexpression of aSyn 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 alpha Syn-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 aSyn 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 aSyn 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 aSyn, which could represent a promising therapeutic target for this neurodegenerative disorder.
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