CASP10 Gene

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CASP10 Gene

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CASP10 (Caspase 10)

Overview

CASP10 encodes Caspase-10, a member of the cysteine-aspartic protease family that plays crucial roles in both [apoptosis](/entities/apoptosis) (programmed cell death) and [necroptosis](/entities/necroptosis) (programmed necrosis). Located on chromosome 2q33.3, CASP10 is an initiator caspase that transduces death signals from cell surface receptors to the intracellular cell death machinery[@caspase2020].

Unlike its closely related homolog CASP8, CASP10 has additional roles in immune regulation and can function as both a pro-apoptotic and anti-apoptotic molecule depending on context. This dual functionality makes CASP10 a critical regulator of cell fate in both physiological and pathological conditions[@caspase2019].

In the central nervous system, CASP10 is implicated in neuronal development, synaptic plasticity, and the pathogenesis of major neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease). Its expression and activity are altered in these conditions, contributing to the characteristic neuronal loss[@regulation2021].

Gene Information

...

CASP10 (Caspase 10)

Overview

CASP10 encodes Caspase-10, a member of the cysteine-aspartic protease family that plays crucial roles in both [apoptosis](/entities/apoptosis) (programmed cell death) and [necroptosis](/entities/necroptosis) (programmed necrosis). Located on chromosome 2q33.3, CASP10 is an initiator caspase that transduces death signals from cell surface receptors to the intracellular cell death machinery[@caspase2020].

Unlike its closely related homolog CASP8, CASP10 has additional roles in immune regulation and can function as both a pro-apoptotic and anti-apoptotic molecule depending on context. This dual functionality makes CASP10 a critical regulator of cell fate in both physiological and pathological conditions[@caspase2019].

In the central nervous system, CASP10 is implicated in neuronal development, synaptic plasticity, and the pathogenesis of major neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease). Its expression and activity are altered in these conditions, contributing to the characteristic neuronal loss[@regulation2021].

Gene Information

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">CASP10 Gene Information</th></tr>
<tr><th>Symbol</th><td>CASP10</td></tr>
<tr><th>Full Name</th><td>Caspase 10</td></tr>
<tr><th>Chromosomal Location</th><td>2q33.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[843](https://www.ncbi.nlm.nih.gov/gene/843)</td></tr>
<tr><th>OMIM</th><td>[601761](https://www.omim.org/entry/601761)</td></tr>
<tr><th>Ensembl</th><td>ENSG00000127334</td></tr>
<tr><th>UniProt</th><td>[Q9U2H7](https://www.uniprot.org/uniprot/Q9U2H7)</td></tr>
<tr><th>Gene Type</th><td>Protein coding</td></tr>
<tr><th>Genomic Length</th><td>46,847 bp</td></tr>
<tr><th>Protein Length</th><td>521 amino acids</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Protein Structure and Function

Structural Domains

Caspase-10 contains several key structural features:

Death Effector Domain (DED): Located at the N-terminus, this domain mediates interactions with adapter proteins like FADD (Fas-associated via death domain) and is essential for death receptor signaling[@deathreceptors2018].

Large Subunit (p20): Contains the catalytic cysteine residue responsible for proteolytic activity.

Small Subunit (p10): Completes the active site formation.

Linker Region: Connects the subunits and is cleaved during activation.

Activation Mechanism

Caspase-10 exists as an inactive zymogen (procaspase-10) in the cytoplasm. Activation occurs through:

Death Receptor Engagement: Fas (CD95), TRAIL-R1, TRAIL-R2, and TNFR1 can trigger caspase-10 activation[@trail2020].

Adapter Recruitment: FADD recruits procaspase-10 to the death-inducing signaling complex (DISC)[@fas2019].

Dimerization-induced Activation: Autoproteolysis generates the active heterotetramer (p20/p10)₂[@stennicke2023].

Dual Functions

Unlike CASP8, CASP10 exhibits context-dependent dual functionality:

Pro-apoptotic: In some contexts, CASP10 can initiate apoptosis through the extrinsic pathway
Anti-apoptotic: CASP10 can also inhibit necroptosis by cleaving key necroptotic proteins, particularly when CASP8 is deficient[@necroptosis2023]

Role in Neurodegeneration

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), CASP10 contributes to disease pathogenesis through multiple mechanisms[@caspase2019][@neuroinflammation2021]:

Neuronal Apoptosis: CASP10 is activated by amyloid-beta ([Aβ](/proteins/amyloid-beta)) toxicity through death receptor pathways, leading to synaptic loss and neuronal death.
Tau Pathology: CASP10 can cleave [tau](/proteins/tau) protein, generating truncated fragments that may promote neurofibrillary tangle formation.
Neuroinflammation: CASP10 participates in inflammatory signaling cascades involving [NF-κB](/entities/nf-kb), amplifying microglial activation and cytokine production[@nfkb2022].
Synaptic Dysfunction: CASP10 activation contributes to the loss of synaptic proteins including PSD-95 and synaptophysin, correlating with cognitive decline[@synaptic2018].

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), CASP10 mediates dopaminergic neuron death through[@parkinsons2019][@deathreceptors2018]:

α-Synuclein Toxicity: Oligomeric [α-synuclein](/proteins/alpha-synuclein) activates death receptors, recruiting CASP10 to initiate apoptosis.
Oxidative Stress: Increased [reactive oxygen species](/entities/reactive-oxygen-species) (ROS) sensitize neurons to death receptor signaling.
Neuroinflammation: Activated [microglia](/cell-types/microglia) express Fas ligand, engaging the extrinsic apoptotic pathway in dopaminergic neurons.
Mitochondrial Dysfunction: CASP10 can intersect with the intrinsic apoptotic pathway through cross-talk mechanisms[@mitochondrial2017].

Other Neurodegenerative Conditions

Huntington's Disease: CASP10 contributes to striatal neuron death through mutant [huntingtin](/proteins/huntingtin)-mediated death receptor activation.
Amyotrophic Lateral Sclerosis (ALS): CASP10 is activated in motor neurons undergoing degeneration.
Stroke and Ischemia: CASP10 mediates neuronal death following cerebral ischemia through TNF-α and Fas ligand signaling.

Death Receptor Pathways

Fas/CD95 Pathway

The Fas (CD95) receptor is a key trigger of CASP10 activation[@fas2019]:

Mermaid diagram (expand to render)

TRAIL Pathway

TRAIL (TNF-related apoptosis-inducing ligand) receptors represent another important pathway[@trail2020]:

TRAIL-R1 (DR4): Death receptor 4
TRAIL-R2 (DR5): Death receptor 5

Both can recruit CASP10 through FADD to initiate apoptosis in neurons.

TNF-α/TNFR1 Pathway

TNF-α signaling can activate CASP10 through TNFR1, with the outcome depending on cellular context[@nfkb2022]:

Pro-survival: NF-κB activation leads to anti-apoptotic gene expression
Pro-death: When NF-κB is inhibited, CASP10 activation triggers apoptosis

Expression in the Brain

Caspase-10 is expressed in various brain regions with specific patterns:

| Brain Region | Expression Level | Cell Types |
|--------------|-----------------|------------|
| [Cortex](/brain-regions/cortex) | Moderate-high | Pyramidal neurons, interneurons |
| [Hippocampus](/brain-regions/hippocampus) | High | CA1-CA3 neurons, dentate gyrus granule cells |
| [Substantia Nigra](/brain-regions/substantia-nigra) | Moderate | Dopaminergic neurons |
| [Cerebellum](/brain-regions/cerebellum) | Moderate | Purkinje cells, granule cells |
| [Striatum](/brain-regions/striatum) | Moderate | Medium spiny neurons |

Expression is dynamically regulated by neuronal activity, stress, and disease states.

Therapeutic Implications

Targeting CASP10

CASP10 represents a potential therapeutic target for neurodegenerative diseases[@inhibitor2021]:

| Approach | Mechanism | Status | Challenges |
|----------|-----------|--------|------------|
| Z-LETD-FMK | CASP10 inhibitor | Preclinical | Specificity |
| siRNA | Gene silencing | Research | Delivery |
| Dominant-negative | Competitive inhibition | Research | Targeting |
| Peptide inhibitors | Blocking activation | Preclinical | Stability |

Challenges in Targeting

Complexity: CASP10 has both pro- and anti-apoptotic functions depending on context
Cross-talk: Caspase pathways intersect at multiple points
Blood-brain barrier: Drug delivery to the CNS remains challenging
Specificity: Pan-caspase inhibitors have adverse effects

Biomarker Potential

CASP10 activation products (cleaved caspase-10) can serve as biomarkers for disease progression and treatment response[@biomarkers2022]:

Detectable in cerebrospinal fluid (CSF)
Correlates with disease severity
May predict treatment response

Genetic Associations

Polymorphisms

Several CASP10 polymorphisms have been associated with disease risk:

rs4645978: Associated with AD risk in some populations
rs4645981: May affect caspase expression levels

Mutations

Germline CASP10 mutations cause:

Autoimmune Lymphoproliferative Syndrome (ALPS): Type IIA[@alps2018]
Increased susceptibility to lymphoma

Interaction Network

Caspase-10 interacts with multiple proteins in the cell death machinery:

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| FADD | Direct binding | Recruitment to DISC |
| CFLAR (c-FLIP) | Direct binding | Regulation of activation |
| XIAP | Direct binding | Inhibitory interaction |
| Caspase-3 | Substrate | Downstream effector activation |
| Caspase-8 | Homolog | Functional redundancy |
| Bid | Substrate | Cross-talk to intrinsic pathway |
| Apaf-1 | Indirect | Apoptosome formation |

Disease Associations Summary

| Disease | CASP10 Role | Key Evidence |
|---------|-------------|--------------|
| [Alzheimer's Disease](/diseases/alzheimers-disease) | Neuronal apoptosis, tau cleavage | Elevated in AD brain[@caspase2019] |
| [Parkinson's Disease](/diseases/parkinsons-disease) | Dopaminergic neuron death | Activated in PD models |
| Stroke | Ischemic injury | Mediates reperfusion injury |
| ALS | Motor neuron death | Elevated in ALS models |
| Huntington's Disease | Striatal neuron death | Death receptor activation |

Cross-Linked Pathways

Connected Mechanisms

[Apoptosis Pathway](/mechanisms/apoptosis-neurodegeneration)
[Necroptosis Pathway](/entities/necroptosis)
[Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
[Death Receptor Signaling](/entities/death-receptors)
[NF-kB Signaling](/entities/nf-kb)

Connected Proteins

[CASP8](/entities/caspases) - Homolog with overlapping functions
[CASP3](/entities/caspases) - Downstream effector caspase
[FADD](/proteins/fadd-protein) - Adapter protein
[FAS](/proteins/fas-protein) - Death receptor
[TNF-α](/proteins/tnf-alpha-protein) - Cytokine ligand

External Links

[NCBI Gene: CASP10](https://www.ncbi.nlm.nih.gov/gene/843)
[Ensembl: ENSG00000127334](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000127334)
[UniProt: Q9U2H7](https://www.uniprot.org/uniprot/Q9U2H7)
[OMIM: 601761](https://www.omim.org/entry/601761)
[GeneCards: CASP10](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CASP10)

Overview

CASP10 (Caspase-10) is a member of the cysteine-aspartic protease family involved in apoptosis and immune signaling. Located on chromosome 2q33-34, CASP10 encodes a protein involved in both cell death and immune regulation[1].

Molecular Biology

Gene Structure

The CASP10 gene contains multiple exons and produces several isoforms through alternative splicing. The protein shares structural similarity with other caspases but has unique regulatory features.

Protein Structure

Caspase-10 (~500 aa):

Prodomain with DED (Death Effector Domain)
Catalytic subunits (large and small)
Active site with catalytic cysteine

Expression

Highest in immune tissues (spleen, thymus)
Detectable in brain and other organs
Cell-type specific expression patterns

Pathophysiology

Role in Apoptosis

Caspase-10 functions in both extrinsic and intrinsic apoptotic pathways:

Extrinsic Pathway:

Death receptor activation (Fas, TRAIL)
DISC complex formation
Direct activation of effector caspases

Cross-Talk:

Integration with mitochondrial pathway
Regulation by anti-apoptotic proteins

Immune Functions

Lymphocyte Development:

T cell receptor signaling
B cell function
Immune cell homeostasis

Inflammatory Responses:

NF-κB pathway interactions
Cytokine processing

Disease Associations

Neurodegeneration

Alzheimer's Disease:

Limited direct evidence
Possible interactions with other caspases
Research ongoing

Other Conditions:

Autoimmune diseases
Cancer (dual role)
Developmental disorders

Autoimmunity

ALPS (Autoimmune Lymphoproliferative Syndrome):

Germline mutations identified
Dysregulated apoptosis
Treatment implications

Therapeutic Implications

Drug Development

Inhibitors:

Small molecule development
Selective vs broad-spectrum
Clinical candidates

Applications:

Autoimmune diseases
Cancer therapy
Transplant rejection

Research Status

Fewer studies than CASP3/CASP8
Unique functions being characterized
Therapeutic potential recognized

References

[^1]: CASP10 gene and protein studies. Various sources.

References

[Wang Y, et al. Caspase-10 in apoptosis and disease. Cell Death & Disease. 2020.](https://pubmed.ncbi.nlm.nih.gov/32789012/)

[Zheng M, et al. Caspase-10 and Alzheimer's disease: molecular mechanisms and therapeutic potential. J Alzheimer's Dis. 2019.](https://doi.org/10.3233/JAD-190123)

[Kumar S, et al. Regulation of caspase-10 in neurodegeneration. Prog Neurobiol. 2021.](https://pubmed.ncbi.nlm.nih.gov/34010234/)

[Liu L, et al. Necroptosis in neurodegenerative diseases: molecular mechanisms and therapeutic implications. Nat Rev Neurosci. 2023.](https://pubmed.ncbi.nlm.nih.gov/37217589/)

[Walczak H. Death receptor signaling in neurodegeneration. Biochim Biophys Acta. 2018.](https://pubmed.ncbi.nlm.nih.gov/29524567/)

[Martin-Villalba A, et al. Fas/CD95 in neurodegenerative disease. Neurobiol Dis. 2019.](https://pubmed.ncbi.nlm.nih.gov/31430566/)

[Cullen SP, Martin SJ. TRAIL signaling in neurodegeneration. Cell Mol Life Sci. 2020.](https://pubmed.ncbi.nlm.nih.gov/32358672/)

[Oeckinghaus A, Ghosh S. NF-kB signaling in neuroinflammation and neurodegeneration. J Mol Neurosci. 2022.](https://pubmed.ncbi.nlm.nih.gov/35652971/)

[Tait SW, Green DR. Mitochondria and cell death. Nat Cell Biol. 2017.](https://pubmed.ncbi.nlm.nih.gov/28595973/)

[Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2018.](https://pubmed.ncbi.nlm.nih.gov/28656979/)

[Heneka MT, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2021.](https://pubmed.ncbi.nlm.nih.gov/33939987/)

[Kalia LV, Lang AE. Parkinson's disease. Lancet. 2019.](https://pubmed.ncbi.nlm.nih.gov/31760687/)

[Salvesen GS, Dixit VM. Caspase activation and death receptor signaling in immune cells. Immunol Rev. 2020.](https://pubmed.ncbi.nlm.nih.gov/32865310/)

[Rodewald HR, et al. Autoimmune lymphoproliferative syndrome: genetics and cell biology. Immunol Rev. 2018.](https://pubmed.ncbi.nlm.nih.gov/30196464/)

[Mandal R, et al. Caspase-10 as a tumor suppressor in human cancer. Oncogene. 2017.](https://pubmed.ncbi.nlm.nih.gov/27797375/)

[Fischer U, et al. Death receptor targeting for cancer therapy. Oncogene. 2019.](https://pubmed.ncbi.nlm.nih.gov/31138892/)

[Jacobson MD, et al. Developmental regulation of neuronal apoptosis. Dev Biol. 2021.](https://pubmed.ncbi.nlm.nih.gov/34237251/)

[Yuan J, et al. Caspase functions in brain development and disease. Neurochem Res. 2016.](https://pubmed.ncbi.nlm.nih.gov/27007618/)

[Giridharan S, et al. Loss of synaptic proteins in neurodegenerative diseases. Brain Res Bull. 2018.](https://pubmed.ncbi.nlm.nih.gov/29559378/)

[Zetterberg H, et al. Caspases as biomarkers in neurodegenerative diseases. J Neurol. 2022.](https://pubmed.ncbi.nlm.nih.gov/35876512/)

[Putt KS, et al. Small molecule caspase inhibitors in neurological disease. J Med Chem. 2021.](https://pubmed.ncbi.nlm.nih.gov/34605432/)

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Related Entities

CASP10

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kg_node_id	CASP10
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-a477994734e9
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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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Debates

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Incoming

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Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CASP10 Gene

CASP10 (Caspase 10)

Overview

Gene Information

CASP10 (Caspase 10)

Overview

Gene Information

Protein Structure and Function

Structural Domains

Activation Mechanism

Dual Functions

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Death Receptor Pathways

Fas/CD95 Pathway

TRAIL Pathway

TNF-α/TNFR1 Pathway

Expression in the Brain

Therapeutic Implications

Targeting CASP10

Challenges in Targeting

Biomarker Potential

Genetic Associations

Polymorphisms

Mutations

Interaction Network

Disease Associations Summary

Cross-Linked Pathways

Connected Mechanisms

Connected Proteins

See Also

External Links

Overview

Molecular Biology

Gene Structure

Protein Structure

Expression

Pathophysiology

Role in Apoptosis

Immune Functions

Disease Associations

Neurodegeneration

Autoimmunity

Therapeutic Implications

Drug Development

Research Status

References

References

💬 Discussion