Lipid Peroxidation Product 4-Hydroxy-2-Nonenal Promotes Seeding-Capable Oligomer Formation and Cell-to-Cell Transfer of α-Synuclein

Aims: Abnormal accumulation of alpha-synuclein aggregates is one of the key pathological features of many neurodegenerative movement disorders and dementias. These pathological aggregates propagate into larger brain regions as the disease progresses, with the associated clinical symptoms becoming increasingly severe and complex. However, the factors that induce alpha-synuclein aggregation and spreading of the aggregates remain elusive. Herein, we have evaluated the effects of the major lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE) on alpha-synuclein oligomerization and cell-to-cell transmission of this protein. Results: Incubation with HNE promoted the oligomerization of recombinant human alpha-synuclein via adduct formation at the lysine and histidine residues. HNE-induced alpha-synuclein oligomers evidence a little beta-sheet structure and are distinct from amyloid fibrils at both conformation and ultrastructure levels. Nevertheless, the HNE-induced oligomers are capable of seeding the amyloidogenesis of monomeric alpha-synuclein under in vitro conditions. When neuronal cells were treated with HNE, both the translocation of alpha-synuclein into vesicles and the release of this protein from cells were increased. Neuronal cells can internalize HNE-modified alpha-synuclein oligomers, and HNE treatment increased the cell-to-cell transfer of alpha-synuclein proteins. Innovation and Conclusion: These results indicate that HNE induces the oligomerization of alpha-synuclein through covalent modification and promotes the cell-to-cell transfer of seeding-capable oligomers, thereby contributing to both the initiation and spread of alpha-synuclein aggregates. Antioxid. Redox Signal. 18, 770-783.