CASP10 encodes Caspase-10, a member of the cysteine-aspartic protease family that plays crucial roles in both apoptosis (programmed cell death) and 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[1].
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[2].
In the central nervous system, CASP10 is implicated in neuronal development, synaptic plasticity, and the pathogenesis of major neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Its expression and activity are altered in these conditions, contributing to the characteristic neuronal loss[3].
| CASP10 Gene Information | |
|---|---|
| Symbol | CASP10 |
| Full Name | Caspase 10 |
| Chromosomal Location | 2q33.3 |
| NCBI Gene ID | [843](https://www.ncbi.nlm.nih.gov/gene/843) |
| OMIM | [601761](https://www.omim.org/entry/601761) |
| Ensembl | ENSG00000127334 |
| UniProt | [Q9U2H7](https://www.uniprot.org/uniprot/Q9U2H7) |
| Gene Type | Protein coding |
| Genomic Length | 46,847 bp |
| Protein Length | 521 amino acids |
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[4].
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.
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[5].
Adapter Recruitment: FADD recruits procaspase-10 to the death-inducing signaling complex (DISC)[6].
Dimerization-induced Activation: Autoproteolysis generates the active heterotetramer (p20/p10)₂[7].
Unlike CASP8, CASP10 exhibits context-dependent dual functionality:
In Alzheimer's disease, CASP10 contributes to disease pathogenesis through multiple mechanisms[2:1][9]:
In Parkinson's disease, CASP10 mediates dopaminergic neuron death through[12][4:1]:
The Fas (CD95) receptor is a key trigger of CASP10 activation[6:1]:
TRAIL (TNF-related apoptosis-inducing ligand) receptors represent another important pathway[5:1]:
Both can recruit CASP10 through FADD to initiate apoptosis in neurons.
TNF-α signaling can activate CASP10 through TNFR1, with the outcome depending on cellular context[10:1]:
Caspase-10 is expressed in various brain regions with specific patterns:
| Brain Region | Expression Level | Cell Types |
|---|---|---|
| Cortex | Moderate-high | Pyramidal neurons, interneurons |
| Hippocampus | High | CA1-CA3 neurons, dentate gyrus granule cells |
| Substantia Nigra | Moderate | Dopaminergic neurons |
| Cerebellum | Moderate | Purkinje cells, granule cells |
| Striatum | Moderate | Medium spiny neurons |
Expression is dynamically regulated by neuronal activity, stress, and disease states.
CASP10 represents a potential therapeutic target for neurodegenerative diseases[14]:
| 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 |
CASP10 activation products (cleaved caspase-10) can serve as biomarkers for disease progression and treatment response[15]:
Several CASP10 polymorphisms have been associated with disease risk:
Germline CASP10 mutations cause:
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 | CASP10 Role | Key Evidence |
|---|---|---|
| Alzheimer's Disease | Neuronal apoptosis, tau cleavage | Elevated in AD brain[2:2] |
| Parkinson's 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 |
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].
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.
Caspase-10 (~500 aa):
Caspase-10 functions in both extrinsic and intrinsic apoptotic pathways:
Extrinsic Pathway:
Cross-Talk:
Lymphocyte Development:
Inflammatory Responses:
Alzheimer's Disease:
Other Conditions:
ALPS (Autoimmune Lymphoproliferative Syndrome):
Inhibitors:
Applications:
Wang Y, et al. Caspase-10 in apoptosis and disease. Cell Death & Disease. 2020. ↩︎
Zheng M, et al. Caspase-10 and Alzheimer's disease: molecular mechanisms and therapeutic potential. Journal of Alzheimer's Disease. 2019. ↩︎ ↩︎ ↩︎
Kumar S, et al. Regulation of caspase-10 in neurodegeneration. Progress in Neurobiology. 2021. ↩︎
Walczak H. Death receptor signaling in neurodegeneration. Biochimica et Biophysica Acta. 2018. ↩︎ ↩︎
Cullen SP, Martin SJ. TRAIL signaling in neurodegeneration. Cellular and Molecular Life Sciences. 2020. ↩︎ ↩︎
Martin-Villalba A, et al. Fas/CD95 in neurodegenerative disease. Neurobiology of Disease. 2019. ↩︎ ↩︎
Stennicke FR, et al. Caspase-10 isoforms and their differential regulation. Cell Death & Differentiation. 2023. ↩︎
Liu L, et al. Necroptosis in neurodegenerative diseases: molecular mechanisms and therapeutic implications. Nature Reviews Neuroscience. 2023. ↩︎
Heneka MT, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurology. 2021. ↩︎
Oeckinghaus A, Ghosh S. NF-kB signaling in neuroinflammation and neurodegeneration. Journal of Molecular Neuroscience. 2022. ↩︎ ↩︎
Giridharan S, et al. Loss of synaptic proteins in neurodegenerative diseases. Brain Research Bulletin. 2018. ↩︎
Kalia LV, Lang AE. Parkinson's disease. The Lancet. 2019. ↩︎
Tait SW, Green DR. Mitochondria and cell death. Nature Cell Biology. 2017. ↩︎
Putt KS, et al. Small molecule caspase inhibitors in neurological disease. Journal of Medicinal Chemistry. 2021. ↩︎
Zetterberg H, et al. Caspases as biomarkers in neurodegenerative diseases. Journal of Neurology. 2022. ↩︎
Rodewald HR, et al. Autoimmune lymphoproliferative syndrome: genetics and cell biology. Immunological Reviews. 2018. ↩︎