Alpha-Synuclein Regulates Neuronal Levels of Manganese and Calcium

详细信息    查看全文

• 作者：Tanja Du膷i膰 ; Eleonora Carboni ; Barry Lai ; Si Chen ; Bernhard Michalke ; Diana F. L谩zaro ; Tiago F. Outeiro ; Mathias B盲hr ; Elisabeth Barski ; Paul Lingor
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：October 21, 2015
• 年：2015
• 卷：6
• 期：10
• 页码：1769-1779
• 全文大小：803K
• ISSN：1948-7193

文摘

Manganese (Mn) may foster aggregation of alpha-synuclein (伪Syn) contributing to the pathogenesis of PD. Here, we examined the influence of 伪Syn 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 伪Syn 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 伪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 伪Syn 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 伪Syn 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 伪Syn, which could represent a promising therapeutic target for this neurodegenerative disorder.