title: Lipid peroxidation product 4-hydroxy-2-nonenal promotes seeding-capable oligomer formation and cell-to-cell transfer of α-synuclein.
abstract: OBJECTIVE
  Abnormal accumulation of α-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 α-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 α-synuclein oligomerization and cell-to-cell transmission of this protein.
  
  
  RESULTS
  Incubation with HNE promoted the oligomerization of recombinant human α-synuclein via adduct formation at the lysine and histidine residues. HNE-induced α-synuclein oligomers evidence a little β-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 α-synuclein under in vitro conditions. When neuronal cells were treated with HNE, both the translocation of α-synuclein into vesicles and the release of this protein from cells were increased. Neuronal cells can internalize HNE-modified α-synuclein oligomers, and HNE treatment increased the cell-to-cell transfer of α-synuclein proteins.
  
  
  CONCLUSIONS
  These results indicate that HNE induces the oligomerization of α-synuclein through covalent modification and promotes the cell-to-cell transfer of seeding-capable oligomers, thereby contributing to both the initiation and spread of α-synuclein aggregates.
authors.affiliation: Department of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Bae
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Ho
authors.forename: Eunbi
authors.initials: E
authors.lastname: Park
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Jung
authors.forename: Kyungcho
authors.initials: K
authors.lastname: Cho
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Hong
authors.forename: He-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D009474:Neurons / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D000682:Amyloid; D051844:alpha-Synuclein; C027576:4-hydroxy-2-nonenal