TY - JOUR
T1 - Oxidative stress-induced posttranslational modifications of alpha-synuclein
T2 - Specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity
AU - Xiang, Wei
AU - Schlachetzki, Johannes C.M.
AU - Helling, Stefan
AU - Bussmann, Julia C.
AU - Berlinghof, Marvin
AU - Schäffer, Tilman E.
AU - Marcus, Katrin
AU - Winkler, Jürgen
AU - Klucken, Jochen
AU - Becker, Cord Michael
N1 - Funding Information:
This study was supported by the Deutsche Forschungsgemeinschaft ( SFB539/A3 ), European Union ( HEALTH-F4-2008-202088 ), Bavarian State Ministry of Sciences, Research and the Arts (ForNeuroCell), Ministry of Education and Research ( 01GN0979 and 01GS08143 ), the Albert-Raps Foundation, Bavaria California Technology Center (BaCaTeC), and grants of the University Hospital of the University of Erlangen-Nuremberg, Erlangen, Germany (ELAN program No. 08.11.05.1 ; 10.08.18.1 ; and the Interdisciplinary Center for Clinical Research, IZKF, E9). Rosa Weber, Ingmar Henz, Annette Serwotka, and Kathy Pfeiffer are gratefully acknowledged for their excellent technical assistance. There is no conflict of interest to declare for all authors.
PY - 2013/5
Y1 - 2013/5
N2 - Aggregation and neurotoxicity of misfolded alpha-synuclein (αSyn) are crucial mechanisms for progressive dopaminergic neurodegeneration associated with Parkinson's disease (PD). Posttranslational modifications (PTMs) of αSyn caused by oxidative stress, including modification by 4-hydroxy-2-nonenal (HNE-αSyn), nitration (n-αSyn), and oxidation (o-αSyn), have been implicated to promote oligomerization of αSyn. However, it is yet unclear if these PTMs lead to different types of oligomeric intermediates. Moreover, little is known about which PTM-derived αSyn species exerts toxicity to dopaminergic cells. In this study, we directly compared aggregation characteristics of HNE-αSyn, n-αSyn, and o-αSyn. Generally, all of them promoted αSyn oligomerization. Particularly, HNE-αSyn and n-αSyn were more prone to forming oligomers than unmodified αSyn. Moreover, these PTMs prevented the formation of amyloid-like fibrils, although HNE-αSyn and o-αSyn were able to generate protofibrillar structures. The cellular effects associated with distinct PTMs were studied by exposing modified αSyn to dopaminergic Lund human mesencephalic (LUHMES) neurons. The cellular toxicity of HNE-αSyn was significantly higher than other PTM species. Furthermore, we tested the toxicity of HNE-αSyn 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-αSyn-treated LUHMES cells. We observed a selective toxicity of HNE-αSyn to neurons with higher TH expression. Further mechanistic studies showed that HNE-modification apparently increased the interaction of extracellular αSyn with neurons. Moreover, exposure of differentiated LUHMES cells to HNE-αSyn triggered the production of intracellular reactive oxygen species, preceding neuronal cell death. Antioxidant treatment effectively protected cells from the damage triggered by HNE-αSyn. Our findings suggest a specific pathological effect of HNE-αSyn on dopaminergic neurons.
AB - Aggregation and neurotoxicity of misfolded alpha-synuclein (αSyn) are crucial mechanisms for progressive dopaminergic neurodegeneration associated with Parkinson's disease (PD). Posttranslational modifications (PTMs) of αSyn caused by oxidative stress, including modification by 4-hydroxy-2-nonenal (HNE-αSyn), nitration (n-αSyn), and oxidation (o-αSyn), have been implicated to promote oligomerization of αSyn. However, it is yet unclear if these PTMs lead to different types of oligomeric intermediates. Moreover, little is known about which PTM-derived αSyn species exerts toxicity to dopaminergic cells. In this study, we directly compared aggregation characteristics of HNE-αSyn, n-αSyn, and o-αSyn. Generally, all of them promoted αSyn oligomerization. Particularly, HNE-αSyn and n-αSyn were more prone to forming oligomers than unmodified αSyn. Moreover, these PTMs prevented the formation of amyloid-like fibrils, although HNE-αSyn and o-αSyn were able to generate protofibrillar structures. The cellular effects associated with distinct PTMs were studied by exposing modified αSyn to dopaminergic Lund human mesencephalic (LUHMES) neurons. The cellular toxicity of HNE-αSyn was significantly higher than other PTM species. Furthermore, we tested the toxicity of HNE-αSyn 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-αSyn-treated LUHMES cells. We observed a selective toxicity of HNE-αSyn to neurons with higher TH expression. Further mechanistic studies showed that HNE-modification apparently increased the interaction of extracellular αSyn with neurons. Moreover, exposure of differentiated LUHMES cells to HNE-αSyn triggered the production of intracellular reactive oxygen species, preceding neuronal cell death. Antioxidant treatment effectively protected cells from the damage triggered by HNE-αSyn. Our findings suggest a specific pathological effect of HNE-αSyn on dopaminergic neurons.
KW - Aggregation
KW - Alpha-synuclein
KW - Dopaminergic neuron
KW - Oxidative stress
KW - Parkinson's disease
KW - Posttranslational modification
UR - http://www.scopus.com/inward/record.url?scp=84874372615&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2013.01.004
DO - 10.1016/j.mcn.2013.01.004
M3 - Article
C2 - 23369945
AN - SCOPUS:84874372615
SN - 1044-7431
VL - 54
SP - 71
EP - 83
JO - Molecular and Cellular Neurosciences
JF - Molecular and Cellular Neurosciences
ER -