SOD1 (Superoxide Dismutase 1) is a 154-amino acid copper/zinc-binding enzyme that catalyzes the dismutation of superoxide radical (O₂⁻) to hydrogen peroxide (H₂O₂) and molecular oxygen (O₂). This enzyme is a critical component of cellular antioxidant defense and is centrally implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
SOD1 is a homodimeric protein with each subunit containing:
- One copper ion (catalytic core)
- One zinc ion (structural stability)
- One intracellular disulfide bond (Cys57-Cys146)
| Feature | Details |
|---------|---------|
| Molecular Weight | ~32 kDa (dimer) |
| Subunit Size | 16 kDa (154 aa) |
| Metal Binding | Cu²⁺ (catalytic), Zn²⁺ (structural) |
| Disulfide Bond | Cys57-Cys146 |
| PDB Structures | 1HL5, 1HL4, 2C9S, 2Zycl |
SOD1 adopts multiple conformational states:
- Apo-state (metal-free)
- Holo-state (fully loaded with Cu and Zn)
- Partially metalated states
- Mutant PRESENT states (ALS-associated)
SOD1 catalyzes the dismutation reaction:
2O₂⁻ + 2H⁺ → H₂O₂ + O₂
This reaction occurs through a cyclic mechanism involving:
- Reduction of Cu²⁺ to Cu⁺ by superoxide
- Oxidation of Cu⁺ back to Cu²⁺ by another superoxide
- Release of hydrogen peroxide
Beyond superoxide scavenging, SOD1 participates in:
- Redox signaling
- Iron metabolism
- Mitochondrial function
- Immune response
- Cellular proteostasis
Over 190 SOD1 mutations cause familial ALS, including:
- A4V (most common in North America)
- G93A (most studied experimental mutation)
- H46R (common in Japan)
- G86R (common in Sweden)
¶ Misfolding and Aggregation
Mutant SOD1 forms toxic species:
- Soluble oligomers
- Insoluble aggregates
- Sequestration of cellular proteins
Mutations disrupt:
- Enzymatic activity
- Dimer stability
- Metal binding capacity
Mutant SOD1 acquires toxic properties:
- Mitochondrial dysfunction
- ER stress
- Axonal transport defects
- Glial cell activation
SOD1 ALS shares pathways with:
- SOD1 activity altered in AD brain
- may contribute to oxidative stress
- Interaction with amyloid-β
- Reduced SOD1 activity in PD brain
- Associations with PINK1, Parkin pathways
- Mitochondrial dysfunction
- Cancer (altered expression)
- Diabetes (vascular complications)
- Aging (oxidative stress)
- ASOs targeting SOD1 mRNA
- siRNA delivery
- CRISPR-based approaches
- Copper chelators
- Protein aggregators
- Antioxidants
- Anti-SOD1 antibodies
- Vaccine approaches
| Trial |
Compound |
Phase |
Status |
| NCT00761847 |
BIIB067 |
1/2 |
Completed |
| NCT03070119 |
BIIB067 |
3 |
Ongoing |
| NCT04449650 |
AP-002 |
1 |
Recruiting |
- Total SOD1 levels
- Mutant-specific SOD1
- Post-translational modifications
- PET ligands for SOD1 aggregates (experimental)
- MR spectroscopy
- SOD1 G93A mice (most common)
- SOD1 G37R mice
- SOD1 H46R mice
- Progressive motor neuron loss
- Muscle denervation
- Shorter lifespan
- Glial activation
- Commercial panels available
- Prenatal testing possible
- Preimplantation genetic diagnosis
- SOD1 activity assays
- Mutation analysis
- Protein levels