Changes in secondary structure of α-synuclein during oligomerization induced by reactive aldehydes

Yixiao Cai, Christofer Lendel, Lars Österlund, Alex Kasrayan, Lars Lannfelt, Martin Ingelsson, Fredrik Nikolajeff, Mikael Karlsson, Joakim Bergström*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


The oxidative stress-related reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) have been shown to promote formation of α-synuclein oligomers in vitro. However, the changes in secondary structure of α-synuclein and the kinetics of the oligomerization process are not known and were the focus of this study. Size exclusion chromatography showed that after 1 h of incubation, HNE induced the formation of an oligomeric α-synuclein peak with a molecular weight of about ∼2000 kDa, which coincided with a decreasing ∼50 kDa monomeric peak. With prolonged incubation (up to 24 h) the oligomeric peak became the dominating molecular species. In contrast, in the presence of ONE, a ∼2000 oligomeric peak was exclusively observed after 15 min of incubation and this peak remained constant with prolonged incubation. Western blot analysis of HNE-induced α-synuclein oligomers showed the presence of monomers (15 kDa), SDS-resistant low molecular (30-160 kDa) and high molecular weight oligomers (≥260 kDa), indicating that the oligomers consisted of both covalent and non-covalent protein. In contrast, ONE-induced α-synuclein oligomers only migrated as covalent cross-linked high molecular-weight material (≥300 kDa). Both circular dichroism (CD) and Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy showed that the formation of HNE- and ONE-induced oligomers coincided with a spectral change from random coil to β-sheet. However, ONE-induced α-synuclein oligomers exhibited a slightly higher degree of β-sheet. Taken together, our results indicate that both HNE and ONE induce a change from random coil to β-sheet structure that coincides with the formation of α-synuclein oligomers; albeit through different kinetic pathways depending on the degree of cross-linking.

Original languageEnglish
Pages (from-to)336-341
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number1
Publication statusPublished - 14 Aug 2015
Externally publishedYes


  • 4-Hydroxy-2-nonenal
  • 4-Oxo-2-nonenal
  • Aggregation
  • Alpha-synuclein
  • Amyloid
  • Dementia with Lewy bodies
  • Oligomers
  • Oxidative stress
  • Parkinson's disease

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