Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity

Journal article

Publication Details

Author(s): Xiang W, Menges S, Schlachetzki J, Meixner H, Hoffmann AC, Schlötzer-Schrehardt U, Becker CM, Winkler J, Klucken J, Klucken J
Journal: Molecular Neurodegeneration
Publication year: 2015
Volume: 10
Pages range: 8
ISSN: 1750-1326


Aggregation and aggregation-mediated formation of toxic alpha synuclein (aSyn) species have been linked to the pathogenesis of sporadic and monogenic Parkinson's disease (PD). A novel H50Q mutation of aSyn, resulting in the substitution of histidine by glutamine, has recently been identified in PD patients. We have previously shown that the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) induces the formation of HNE-aSyn adducts, thereby promoting aSyn oligomerization and increasing its extracellular toxicity to human dopaminergic neurons. Intriguingly, we identified histidine 50 (H50) of aSyn as one of the HNE modification target residues. These converging lines of evidence support the hypothesis that changes in H50 via posttranslational modification (PTM) and mutation trigger the formation of aggregated, toxic aSyn species, which interfere with cellular homeostasis. In the present study, we aim to elucidate 1) the role of H50 in HNE-mediated aSyn aggregation and toxicity, and 2) the impact of H50 mutation on aSyn pathology. Besides the PD-related H50Q, we analyze a PD-unrelated control mutation, in which H50 is replaced by an arginine residue (H50R).Analysis of HNE-treated aSyn revealed that H50 is the most susceptible residue of aSyn to HNE modification and is crucial for HNE-mediated aSyn oligomerization. Overexpression of aSyn with substituted H50 in H4 neuroglioma cells reduced HNE-induced cell damage, indicating a pivotal role of H50 in HNE modification-induced aSyn toxicity. Furthermore, we showed in vitro that H50Q/R mutations substantially increase the formation of high density and fibrillar aSyn species, and potentiate the oligomerization propensity of aSyn in the presence of a nitrating agent. Cell-based experiments also revealed that overexpression of H50Q aSyn in H4 cells promotes aSyn oligomerization. Importantly, overexpression of both H50Q/R aSyn mutants in H4 cells significantly increased cell death when compared to wild type aSyn. This increase in cell death was further exacerbated by the application of H2O2.A dual approach addressing alterations of H50 showed that either H50 PTM or mutation trigger aSyn aggregation and toxicity, suggesting an important role of aSyn H50 in the pathogenesis of both sporadic and monogenic PD.

FAU Authors / FAU Editors

Becker, Cord-Michael Prof. Dr.
Medizinische Fakultät
Hoffmann, Anna-Carin
Interdisziplinäres Zentrum für Klinische Forschung IZKF Prof.Dr.Kalden Medizinische Klinik 3
Klucken, Jochen Prof. Dr.
Medizinische Fakultät
Klucken, Jochen Prof. Dr.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Menges, Stefanie
Professur für Molekulare Neurologie
Schlachetzki, Johannes Dr. med.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Schlötzer-Schrehardt, Ursula apl. Prof. Dr.
Medizinische Fakultät
Winkler, Jürgen Prof. Dr.
Professur für Molekulare Neurologie
Xiang, Wei PD Dr.
Lehrstuhl für Biochemie und Molekulare Medizin

How to cite

Xiang, W., Menges, S., Schlachetzki, J., Meixner, H., Hoffmann, A.-C., Schlötzer-Schrehardt, U.,... Klucken, J. (2015). Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity. Molecular Neurodegeneration, 10, 8.

Xiang, Wei, et al. "Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity." Molecular Neurodegeneration 10 (2015): 8.


Last updated on 2018-05-10 at 02:32