Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Cu, Zn-superoxide dismutase (SOD1) aggregation is implicated in amyotrophic lateral sclerosis (ALS).
• The role of cysteine overoxidation in SOD1 filament formation remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism of SOD1 filament formation via cysteine overoxidation in sporadic ALS (sALS).
• To investigate the structural and functional consequences of mimicking cysteine overoxidation in SOD1.

Main Methods:

• Determined the crystal structure of a double mutant (C57D/C146D) SOD1 mimicking cysteine overoxidation.
• Assessed filament formation of wild-type and mutant SOD1 proteins.
• Investigated the effect of hypochlorous acid (HOCl) treatment on SOD1 filamentation.

Main Results:

• The crystal structure revealed an open, relaxed conformation of loop IV in the double mutant SOD1.
• The C57D/C146D SOD1 mutant exhibited increased filament formation and promoted wild-type SOD1 aggregation.
• HOCl treatment significantly facilitated filament formation in wild-type SOD1 proteins.

Conclusions:

• Overoxidized SOD1 acts as a triggering factor in sporadic ALS pathogenesis.
• This study proposes a molecular mechanism for SOD1 filament formation driven by oxidative stress.
• Findings contribute to understanding neurodegenerative disorders associated with reactive oxygen species (ROS).