| Author(s): |
Dantas, Lucas S.
[1]
;
Viviani, Lucas G.
[2]
;
Inague, Alex
[1]
;
Piccirillo, Erika
[2, 1]
;
Rezende, Leandro de
[2]
;
Ronsein, Graziella E.
[1]
;
Augusto, Ohara
[1]
;
Medeiros, Marisa H. G.
[1]
;
Amaral, Antonia T. do
[2]
;
Miyamoto, Sayuri
[1]
Total Authors: 10
|
| Affiliation: | [1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Ave Prof Lineu Prestes 748, BR-05508000 Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Sao Paulo, SP - Brazil
Total Affiliations: 2
|
Unsaturated lipids are oxidized by reactive oxygen species and enzymes, leading to the increased formation of lipid hydroperoxides and several electrophilic products. Lipid-derived electrophiles can modify macromolecules, such as proteins, resulting in the loss of function and/or aggregation. The accumulation of Cu,Zn-superoxide dismutase (SOD1) aggregates has been associated with familial cases of amyotrophic lateral sclerosis (ALS). The protein aggregation mechanisms in motor neurons remain unclear, although recent studies have shown that lipids and oxidized lipid derivatives may play roles in this process. Here, we aimed to compare the effects of different lipid aldehydes on the induction of SOD1 modifications and aggregation, in vitro. Human recombinant apo-SOD1 was incubated with 4-hydroxy-2-hexenal (HHE), 4-hydroxy-2-nonenal (HNE), 2-hexen-1-al (HEX), 2,4-nonadienal (NON), 2,4-decadienal (DEC), or secosterol aldehydes (SECO-A or SECO-B). High-molecular weight apo-SOD1 aggregates dramatically increased in the presence of highly hydrophobic aldehydes (LogPcalc 3). Notably, several Lys residues were modified by exposure to all aldehydes. The observed modifications were primarily observed on Lys residues located near the dimer interface (K3 and K9) and at the electrostatic loop (K122, K128, and K136). Moreover, HHE and HNE induced extensive apo-SOD1 modifications, by forming Schiff bases or Michael adducts with Lys, His, and Cys residues. However, these aldehydes were unable to induce large protein aggregates. Overall, our data shed light on the importance of lipid aldehyde hydrophobicity on the induction of apo-SOD1 aggregation and identified preferential sites of lipid aldehyde induced modifications. (AU) |