Lipid aldehyde hydrophobicity affects apo-SOD1 modification and aggregation

Area of Science:

• Biochemistry
• Neuroscience
• Oxidative Stress

Background:

• Unsaturated lipids oxidize into reactive electrophilic products.
• Lipid derivatives can modify proteins, leading to dysfunction and aggregation.
• Accumulation of copper-zinc superoxide dismutase (SOD1) aggregates is linked to familial amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

• To investigate the role of lipid aldehyde hydrophobicity in SOD1 modification and aggregation.
• To compare the in vitro effects of various lipid aldehydes on human recombinant apo-SOD1.

Main Methods:

• Incubation of human recombinant apo-SOD1 with different lipid aldehydes (HHE, HNE, HEX, NON, DEC, SECO-A, SECO-B).
• Analysis of apo-SOD1 modifications and high-molecular-weight aggregate formation.
• Assessment of aldehyde hydrophobicity (LogPcalc).

Main Results:

• Highly hydrophobic aldehydes (LogPcalc > 3) significantly increased apo-SOD1 aggregation.
• All tested aldehydes modified Lys residues, particularly at the dimer interface (K3, K9) and electrostatic loop (K122, K128, K136).
• HHE and HNE caused extensive modifications (Schiff bases, Michael adducts) on Lys, His, and Cys residues but did not induce large aggregates.

Conclusions:

• Lipid aldehyde hydrophobicity is a critical determinant for inducing apo-SOD1 aggregation.
• Specific lysine residues are preferential sites for lipid aldehyde modification.
• Understanding these interactions provides insight into ALS pathogenesis.