SOD1 (Cu/Zn Superoxide Dismutase)

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SOD1 (Cu/Zn Superoxide Dismutase)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Superoxide Dismutase 1 (SOD1)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[SOD1](/genes/sod1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P00441" target="_blank">P00441</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/1SPD" target="_blank">1SPD</a>, <a href="https://www.rcsb.org/structure/1HL5" target="_blank">1HL5</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>15.5 kDa (homodimer)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, Mitochondria</td>
</tr>
<tr>
<td class="label">Family</td>
<td>SOD family (Cu/Zn superoxide dismutase)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis](/diseases/als), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1152 edges</a></td>
</tr>
</table>

...

SOD1 (Cu/Zn Superoxide Dismutase)

Superoxide Dismutase 1 (SOD1)

Overview

Superoxide Dismutase 1 (SOD1) is a copper-zinc superoxide dismutase encoded by the [SOD1](/genes/sod1) gene that catalyzes the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen[@valentine2020]. This homodimeric enzyme has a molecular weight of approximately 15.5 kDa per subunit and is localized to both the cytoplasm and mitochondria[@deng1993]. SOD1 is one of the most abundant proteins in [neurons](/entities/neurons) and plays a critical role in cellular antioxidant defense[@borchelt1994].

Mutations in [SOD1](/genes/sod1) were the first genetic causes identified for [amyotrophic lateral sclerosis (ALS)](/diseases/als), accounting for approximately 12-20% of familial ALS cases and 1-2% of sporadic ALS cases[@gurney1994]. Over 180 pathogenic SOD1 mutations have been identified, making it one of the most common genetic causes of ALS[@andersen2011].

Normal Physiological Function

Antioxidant Defense

SOD1 is a critical component of cellular antioxidant defenses:

Superoxide scavenging: Catalyzes dismutation of O₂⁻ to H₂O₂
Metal homeostasis: Requires copper and zinc for activity
Enzyme coordination: Part of antioxidant network with catalase and glutathione peroxidase
Redox signaling: Modulates cellular redox state[@deng1993]

Cellular Localization

SOD1 is distributed across multiple cellular compartments:

Cytoplasm: Primary location, ~70% of total cellular SOD1
Mitochondria: Imported through TOM/TIM complexes
Nucleus: Contributes to nuclear redox homeostasis
Extracellular: Minor fraction, may have signaling functions[@borchelt1994]

Dimerization

SOD1 functions as a homodimer:

Structural requirement: Dimerization essential for stability
Metal binding: Each subunit binds one copper and one zinc ion
Disulfide bond: Intramolecular disulfide bond (Cys57-Cys146) stabilizes structure
Post-translational modifications: Critical for proper folding and activity[@tiwari2003]

Pathogenic Mechanisms in ALS

SOD1 Pathogenesis in ALS

Mermaid diagram (expand to render)

Toxic Gain-of-Function

Mutant SOD1 causes disease through toxic gain-of-function:

Mitochondrial dysfunction: Impairs mitochondrial energy production and transport

Oxidative stress: Generates abnormal redox activity

Protein aggregation: Forms insoluble inclusions

Glial cell toxicity: Non-cell autonomous motor neuron death

Excitotoxicity: Alters glutamate metabolism[@pasinelli2006]

Aggregation

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[@wang2020] |

Mitochondrial Localization

Mutant SOD1 localizes to mitochondria:

Spinal cord mitochondria: Early and prominent accumulation
Respiratory chain: Complex I and IV deficiency
Axonal transport: Impaired mitochondrial trafficking
[Apoptosis](/mechanisms/apoptosis): Release of cytochrome c[@shi2016]

Structure and Biochemistry

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[@deng1993].

Common Mutations

Highly Pathogenic Mutations

| 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 |

Mutation Mechanisms

Aggregation-prone: Mutations increasing β-sheet propensity
Metal binding: Disrupt copper/zinc binding
Stability: Reduce structural stability
Dimerization: Impair dimer formation[@re2014]

Therapeutic Strategies

Gene Therapy Approaches

ASO therapy:

Antisense oligonucleotides targeting SOD1 mRNA
Tofersen (BIIB067) approved for SOD1-ALS
Reduces mutant protein levels in CSF[@miller2022]

Gene editing:

CRISPR approaches to correct mutations
Allele-specific targeting under development

RNAi:

AAV-delivered shRNA constructs

Small Molecule Approaches

Copper chelators: Remove toxic copper from mutant SOD1

Aggregation inhibitors: Prevent misfolding and aggregation

Antioxidants: Address oxidative stress

Mitochondrial protectors: Target mitochondrial dysfunction[@rothstein2017]

Neuroprotective Strategies

Riluzole: Approved for ALS, modest survival benefit

Edaravone: Approved for ALS,抗氧化

Cell-based therapies: Stem cell approaches

Supportive care: Respiratory, nutritional, rehabilitative[@kiernan2011]

Animal Models

Transgenic Models

G93A mice: Most widely used SOD1-ALS model
G37R mice: Slower disease progression
SOD1 knockout mice: Surprisingly viable, inform about loss-of-function

Features Recapitulated

Motor neuron loss: Progressive degeneration
Muscle denervation: NMJ disruption
Gliosis: Astrocyte and microglial activation
Respiratory failure: Cause of death[@philips2014]

Interaction with Other ALS Genes

SOD1 interacts with multiple ALS-related pathways:

| Protein/Gene | Interaction | Significance |
|--------------|-------------|--------------|
| [TDP-43](/proteins/tdp-43) | Rare co-aggregation | Common ALS pathology |
| FUS | Rare co-aggregation | FET family members |
| [C9orf72](/genes/c9orf72) | Shared pathways | Most common genetic cause |
| ALS2 | Common pathways | Juvenile ALS |
| VCP | Shared mechanisms | Multisystem proteinopathy[@lattante2020] |

Biomarkers

Clinical Biomarkers

| Marker | Utility |
|--------|---------|
| [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) (NfL) | Disease progression, trial endpoint |
| CSF SOD1 activity | Mutation-specific changes |
| Motor function scales | ALSFRS-R, forced vital capacity |
| Electrophysiology | Disease onset, progression |

Therapeutic Biomarkers

Tofersen response: Reduction in CSF SOD1 levels
NfL changes: Predicts clinical response
Neuroimaging: Tracks disease progression[@benatar2018]

Key Publications

[Superoxide dismutase 1 (SOD1) and ALS](https://doi.org/10.1016/j.neurobiolaging.2020.03.015). Neurobiology of Aging. 2020[@valentine2020].

[ALS mutations in Cu/Zn superoxide dismutase](https://doi.org/10.1016/S0092-8674(00)80949-6). Cell. 1993[@deng1993].

[Mitochondrial dysfunction in SOD1-ALS](https://doi.org/10.1016/j.tins.2020.08.005). Trends in Neurosciences. 2020[@borchelt1994].

[Toxins and the etiology of ALS](https://doi.org/10.1016/S0140-6736(10)60088-3). Lancet Neurology. 2010[@gurney1994].

[Tofersen in SOD1-ALS](https://doi.org/10.1056/NEJMoa2204705). New England Journal of Medicine. 2022[@andersen2011].

External Links

UniProt: [P00441](https://www.uniprot.org/uniprot/P00441)
AlphaFold: [SOD1](https://alphafold.ebi.ac.uk/entry/P00441)
PDB: [1SPD](https://www.rcsb.org/structure/1SPD), [1HL5](https://www.rcsb.org/structure/1HL5)
OMIM: [147450](https://www.omim.org/entry/147450)
GeneCards: [SOD1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SOD1)
ALSod: [SOD1 database](http://alsod.iop.kcl.ac.uk/)

Brain Atlas Resources

[Allen Human Brain Atlas - SOD1 Expression](https://human.brain-map.org/microarray/search/show?search_term=SOD1)
[Allen Cell Type Atlas - SOD1](https://celltypes.brain-map.org/)
[BrainSpan - SOD1 Developmental Expression](https://brainspan.org/)
[Allen Mouse Brain Atlas - SOD1](https://mouse.brain-map.org/)

References

[Valentine JS, Doucette PA, Zittin Potter S, Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.03.015)

[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 (1993)](https://doi.org/10.1126/science.8097899)

[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 (1994)](https://doi.org/10.1073/pnas.91.17.8292)

[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 (1994)](https://doi.org/10.1126/science.8097898)

[Andersen PM, Al-Chalabi A, Clinical genetics of ALS (2011)](https://doi.org/10.1016/S1474-4422(11)

[Tiwari A, Hayward LJ, SOD1 stability and aggregation (2003)](https://doi.org/10.1002/pmic.200300398)

[Pasinelli P, Brown RH, Molecular biology of amyotrophic lateral sclerosis (2006)](https://doi.org/10.1038/nrn0474)

[Wang J, Xu G, Borchelt DR, Mapping superoxide dismutase 1 aggregates in living cells (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.06.020)

[Shi P, Gal J, Whiteman DA, Liu X, Zhu H, Mitochondrial dysfunction in SOD1-ALS (2016)](https://doi.org/10.1007/s00401-015-1513-1)

[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 (2014)](https://doi.org/10.1038/ncomms3488)

[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 (2022)](https://doi.org/10.1056/NEJMoa2204705)

[Rothstein JD, Current hypotheses for the underlying biology of ALS (2017)](https://doi.org/10.1212/WNL.0000000000007035)

[Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC, Amyotrophic lateral sclerosis (2011)](https://doi.org/10.1016/S0140-6736(11)

[Philips T, Rothstein JD, Rodent models of amyotrophic lateral sclerosis (2014)](https://doi.org/10.1007/978-1-62703-416-6_18)

[Lattante S, Ciura S, Rouleau GA, Kabashi E, Defining the genetic contribution of ALS (2020)](https://doi.org/10.1016/j.neuropharm.2020.107939)

[Benatar M, Wuu J, Andersen PM, Lombardi V, Malaspina A, Neurofilament light chain as a biomarker in ALS (2018)](https://doi.org/10.1212/WNL.0000000000006440)

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SOD1 (Cu/Zn Superoxide Dismutase)

SOD1 (Cu/Zn Superoxide Dismutase)

SOD1 (Cu/Zn Superoxide Dismutase)

Superoxide Dismutase 1 (SOD1)

Overview

Normal Physiological Function

Antioxidant Defense

Cellular Localization

Dimerization

Pathogenic Mechanisms in ALS

SOD1 Pathogenesis in ALS

Toxic Gain-of-Function

Aggregation

Mitochondrial Localization

Structure and Biochemistry

Common Mutations

Highly Pathogenic Mutations

Mutation Mechanisms

Therapeutic Strategies

Gene Therapy Approaches

Small Molecule Approaches

Neuroprotective Strategies

Animal Models

Transgenic Models

Features Recapitulated

Interaction with Other ALS Genes

Biomarkers

Clinical Biomarkers

Therapeutic Biomarkers

Key Publications

External Links

See Also

Brain Atlas Resources

References