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

Abstract

Aims: Abnormal accumulation of a-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 a-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 a-synuclein oligomerization and cell-to-cell transmission of this protein. Results: Incubation with HNE promoted the oligomerization of recombinant human a-synuclein via adduct formation at the lysine and histidine residues. HNE-induced a-synuclein oligomers evidence a little b-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 a-synuclein under in vitro conditions. When neuronal cells were treated with HNE, both the translocation of a-synuclein into vesicles and the release of this protein from cells were increased. Neuronal cells can internalize HNE-modified a-synuclein oligomers, and HNE treatment increased the cell-to-cell transfer of a-synuclein proteins. Innovation and Conclusion: These results indicate that HNE induces the oligomerization of a-synuclein through covalent modification and promotes the cell-to-cell transfer of seedingcapable oligomers, thereby contributing to both the initiation and spread of a-synuclein aggregates. Antioxid. Redox Signal. 18,[770][771][772][773][774][775][776][777][778][779][780][781][782][783]

Structural, morphological, and functional diversity of amyloid oligomers

“…Lipid-derived aldehydes such as HNE reacted with a-synuclein to form lysine adducts and promoted formation of either b-sheet-rich [46][47][48] or primarily disordered [49] oligomers, depending on the reaction conditions. Interestingly, oligomers formed after a-synuclein modification with HNE were more stable and less toxic than those formed in the presence of 4-oxo-2-nonenal [47].…”

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

“…Direct modification of α-synuclein by the product of lipid peroxidation, hydroxynonenal (HNE), results in increased production of off-pathway, β-sheet-rich oligomers that are toxic when applied to cultured cells [170], perhaps due in part to their increased capacity to seed further aggregation both within and between cells [171]. These oligomers form following covalent modification of α-synuclein by HNE, likely by Michael addition to Lys and His, although α-synuclein is not cross-linked to itself.…”

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

“…Interestingly, the α-synuclein oligomers induced by HNE and ONE differ in structure, compactness and morphology [21,22]. Furthermore, conflicting results have been reported regarding the secondary structure of HNE-induced α-synuclein oligomers; as they have been suggested to either have an extended β-sheet structure or exhibit a random structure [22,23,24]. In addition, the rate of oligomerization of α-synuclein induced by HNE and ONE has not been fully elucidated.…”

“…Furthermore, a discrepancy regarding the secondary structure of the α-synuclein oligomers formed in the presence of HNE has been reported. They have shown to either have an ordered secondary structure with a high β-sheet content [21,22,23], or a disordered secondary structure with little β-sheet structure [24,25]. The aim of the current study was to characterize the kinetics and the secondary structural changes of HNE-and ONE-induced α-synuclein oligomerization.…”

“…It has been shown that HNE, and the chemically related reactive aldehyde 4-oxo-2-nonenal (ONE) [20], can induce the formation of α-synuclein oligomers in vitro [21,22,23,24,25].…”