Journal article


Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity


Publication Details
Author(s): Xiang W, Schlachetzki J, Helling S, Bussmann JC, Berlinghof M, Schäffer T, Marcus K, Winkler J, Klucken J, Becker CM, Klucken J
Publisher: Elsevier
Publication year: 2013
Volume: 54
Pages range: 71-83
ISSN: 1044-7431

Abstract

Aggregation and neurotoxicity of misfolded alpha-synuclein (?Syn) are crucial mechanisms for progressive dopaminergic neurodegeneration associated with Parkinson's disease (PD). Posttranslational modifications (PTMs) of ?Syn caused by oxidative stress, including modification by 4-hydroxy-2-nonenal (HNE-?Syn), nitration (n-?Syn), and oxidation (o-?Syn), have been implicated to promote oligomerization of ?Syn. However, it is yet unclear if these PTMs lead to different types of oligomeric intermediates. Moreover, little is known about which PTM-derived ?Syn species exerts toxicity to dopaminergic cells. In this study, we directly compared aggregation characteristics of HNE-?Syn, n-?Syn, and o-?Syn. Generally, all of them promoted ?Syn oligomerization. Particularly, HNE-?Syn and n-?Syn were more prone to forming oligomers than unmodified ?Syn. Moreover, these PTMs prevented the formation of amyloid-like fibrils, although HNE-?Syn and o-?Syn were able to generate protofibrillar structures. The cellular effects associated with distinct PTMs were studied by exposing modified ?Syn to dopaminergic Lund human mesencephalic (LUHMES) neurons. The cellular toxicity of HNE-?Syn was significantly higher than other PTM species. Furthermore, we tested the toxicity of HNE-?Syn in dopaminergic LUHMES cells and other cell types with low tyrosine hydroxylase (TH) expression, and additionally analyzed the loss of TH-immunoreactive cells in HNE-?Syn-treated LUHMES cells. We observed a selective toxicity of HNE-?Syn to neurons with higher TH expression. Further mechanistic studies showed that HNE-modification apparently increased the interaction of extracellular ?Syn with neurons. Moreover, exposure of differentiated LUHMES cells to HNE-?Syn triggered the production of intracellular reactive oxygen species, preceding neuronal cell death. Antioxidant treatment effectively protected cells from the damage triggered by HNE-?Syn. Our findings suggest a specific pathological effect of HNE-?Syn on dopaminergic neurons.



How to cite
APA: Xiang, W., Schlachetzki, J., Helling, S., Bussmann, J.C., Berlinghof, M., Schäffer, T.,... Klucken, J. (2013). Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Molecular and Cellular Neuroscience, 54, 71-83. https://dx.doi.org/10.1016/j.mcn.2013.01.004

MLA: Xiang, Wei, et al. "Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity." Molecular and Cellular Neuroscience 54 (2013): 71-83.

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