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Alpha-Synuclein Regulates Neuronal Levels of Manganese and Calcium

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

© 2015 American Chemical Society. 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.


Publication metadata

Author(s): Ducic T, Carboni E, Lai B, Chen S, Michalke B, Lazaro DF, Outeiro TF, Bahr M, Barski E, Lingor P

Publication type: Article

Publication status: Published

Journal: ACS Chemical Neuroscience

Year: 2015

Volume: 6

Issue: 10

Pages: 1769-1779

Online publication date: 18/08/2015

Acceptance date: 01/01/1900

ISSN (print): 1948-7193

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acschemneuro.5b00093

DOI: 10.1021/acschemneuro.5b00093

PubMed id: 26284970


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