| Superoxide Dismutase 1 (SOD1) | |
|---|---|
| Gene | [SOD1](/genes/sod1) |
| UniProt | P00441 |
| PDB | 1SPD, 1HL5 |
| Mol. Weight | 15.5 kDa (homodimer) |
| Localization | Cytoplasm, Mitochondria |
| Family | SOD family (Cu/Zn superoxide dismutase) |
| Diseases | [Amyotrophic Lateral Sclerosis](/diseases/als), [Parkinson's Disease](/diseases/parkinsons-disease) |
Superoxide Dismutase 1 (SOD1) is a copper-zinc superoxide dismutase encoded by the SOD1 gene that catalyzes the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen[1]. This homodimeric enzyme has a molecular weight of approximately 15.5 kDa per subunit and is localized to both the cytoplasm and mitochondria[2]. SOD1 is one of the most abundant proteins in neurons and plays a critical role in cellular antioxidant defense[3].
Mutations in SOD1 were the first genetic causes identified for amyotrophic lateral sclerosis (ALS), accounting for approximately 12-20% of familial ALS cases and 1-2% of sporadic ALS cases[4]. Over 180 pathogenic SOD1 mutations have been identified, making it one of the most common genetic causes of ALS[5].
SOD1 is a critical component of cellular antioxidant defenses:
SOD1 is distributed across multiple cellular compartments:
SOD1 functions as a homodimer:
Mutant SOD1 causes disease through toxic gain-of-function:
Mutant SOD1 forms various aggregates:
| Aggregate Type | Description | Clinical Relevance |
|---|---|---|
| Insoluble aggregates | Misfolded protein deposits | Common in spinal cord |
| Oligomers | Soluble toxic intermediates | Likely most toxic |
| Inclusion bodies | Large protein aggregates | Detected in motor neurons |
| Aggrephagy defects | Impaired clearance | Contributes to accumulation[8] |
Mutant SOD1 localizes to mitochondria:
SOD1 contains several structural features:
| Feature | Description | Function |
|---|---|---|
| β-barrel | 8 antiparallel β-strands | Core structural element |
| Copper site | His46,48,63,120,163 | Catalytic activity |
| Zinc site | His63,71,80,120 | Structural stability |
| Disulfide bond | Cys57-Cys146 | Structural stabilization |
| Dimer interface | Hydrophobic interactions | Dimer formation |
The wild-type SOD1 structure is well-characterized with multiple PDB entries including 1SPD and 1HL5[2:2].
| Mutation | Type | Clinical Features |
|---|---|---|
| A4V | Missense | Most common in North America |
| G93A | Missense | Rapid progression |
| G37R | Missense | Intermediate onset |
| L126Z | Frameshift | Very aggressive |
| D90A | Missense | Variable phenotype |
ASO therapy:
Gene editing:
RNAi:
SOD1 interacts with multiple ALS-related pathways:
| Protein/Gene | Interaction | Significance |
|---|---|---|
| TDP-43 | Rare co-aggregation | Common ALS pathology |
| FUS | Rare co-aggregation | FET family members |
| C9orf72 | Shared pathways | Most common genetic cause |
| ALS2 | Common pathways | Juvenile ALS |
| VCP | Shared mechanisms | Multisystem proteinopathy[15] |
| Marker | Utility |
|---|---|
| Neurofilament light (NfL) | Disease progression, trial endpoint |
| CSF SOD1 activity | Mutation-specific changes |
| Motor function scales | ALSFRS-R, forced vital capacity |
| Electrophysiology | Disease onset, progression |
Valentine JS, Doucette PA, Zittin Potter S. Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. Annual Review of Biochemistry. 2020. ↩︎ ↩︎
Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff E, Hu P, Herzfeldt B, Roos RP, et al. ALS mutations in Cu/Zn superoxide dismutase. Science. 1993. ↩︎ ↩︎ ↩︎ ↩︎
Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu ZS, Wong PC, Brown RH Jr, Price DL, Sisodia SS, Cleveland DW. Superoxide dismutase 1 with mutations linked to familial ALS. Proceedings of the National Academy of Sciences. 1994. ↩︎ ↩︎ ↩︎
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice expressing mutant SOD1. Science. 1994. ↩︎ ↩︎
Andersen PM, Al-Chalabi A. [Clinical genetics of ALS](https://doi.org/10.1016/S1474-4422(11). Lancet Neurology. 2011. ↩︎ ↩︎
Tiwari A, Hayward LJ. SOD1 stability and aggregation. Proteomics. 2003. ↩︎
Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis. Nature Reviews Neuroscience. 2006. ↩︎
Wang J, Xu G, Borchelt DR. Mapping superoxide dismutase 1 aggregates in living cells. Neurobiology of Aging. 2020. ↩︎
Shi P, Gal J, Whiteman DA, Liu X, Zhu H. Mitochondrial dysfunction in SOD1-ALS. Acta Neuropathologica. 2016. ↩︎
Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, Ikiz B, Nagata T, Papadimitriou D, Nagy P, et al. Necroptosis in mutant SOD1 motor neurons. Nature Communications. 2014. ↩︎
Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, et al. Tofersen in patients with SOD1-ALS. New England Journal of Medicine. 2022. ↩︎
Rothstein JD. Current hypotheses for the underlying biology of ALS. Neurology. 2017. ↩︎
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. [Amyotrophic lateral sclerosis](https://doi.org/10.1016/S0140-6736(11). Lancet. 2011. ↩︎
Philips T, Rothstein JD. Rodent models of amyotrophic lateral sclerosis. Methods in Molecular Biology. 2014. ↩︎
Lattante S, Ciura S, Rouleau GA, Kabashi E. Defining the genetic contribution of ALS. Neuropharmacology. 2020. ↩︎
Benatar M, Wuu J, Andersen PM, Lombardi V, Malaspina A. Neurofilament light chain as a biomarker in ALS. Neurology. 2018. ↩︎