CASP7 (Caspase 7)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CASP7 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CASP7</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Caspase 7</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>840</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P55210</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>CASP-7, ECM, MCH3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>10q25.3</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>303 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~35 kDa (proenzyme), ~20 kDa (active subunits)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
Overview
Mermaid diagram (expand to render)
Caspase 7 (CASP7) is an executioner (effector) caspase that plays a critical role in the execution phase of apoptosis. It is a member of the cysteine-aspartic protease family and is closely related to caspase-3, with which it shares significant structural and functional similarity. Caspase-7 is encoded by the CASP7 gene located on chromosome 10q25.3 and is expressed in most tissues, including the brain. As an executioner caspase, it executes the final stages of programmed cell death by cleaving numerous cellular substrates, leading to the characteristic morphological and biochemical features of apoptosis. This page covers the gene's molecular characteristics, activation mechanisms, and roles in neurodegenerative diseases.
Gene Overview
The CASP7 gene consists of 8 exons and encodes a zymogen (procaspase-7) that requires proteolytic cleavage at specific aspartic acid residues for activation. The mature enzyme consists of p20 (large subunit) and p11 (small subunit) subunits that form a heterodimer.
Structure and Catalytic Mechanism
Caspase-7 contains the characteristic caspase fold consisting of a six-stranded β-sheet surrounded by five α-helices[@cormier2017]. The active site contains a catalytic cysteine residue (Cys186) that performs nucleophilic attack on the peptide bond of substrate proteins. Caspase-7 has a substrate specificity preference for the tetrapeptide sequence DXXD (where X is any amino acid), similar to caspase-3.
The three-dimensional structure reveals a shallow active site pocket that accommodates the substrate's P1-P4 residues. The enzyme exists as a dimer of two heterodimers (p20/p11) in its active form.
Activation Mechanisms
Caspase-7 is activated by both the intrinsic (mitochondrial) and extrinsic (death receptor) pathways[@wolf1999]:
Intrinsic (Mitochondrial) Pathway
Cellular stress or DNA damage triggers mitochondrial outer membrane permeabilization (MOMP)
Cytochrome c is released into the cytosol
Cytochrome c binds to Apaf-1, forming the apoptosome
Caspase-9 is activated within the apoptosome
Activated caspase-9 cleaves and activates caspase-7
Active caspase-7 executes apoptosis by cleaving cellular substratesExtrinsic (Death Receptor) Pathway
Extracellular ligands (FasL, TNF-α, TRAIL) bind to their respective death receptors
Death receptor clustering leads to DISC (Death-Inducing Signaling Complex) formation
Caspase-8 is recruited and activated within the DISC
Caspase-8 directly cleaves and activates caspase-7
Active caspase-7 executes apoptosisHierarchy with Other Caspases
Caspase-7 functions downstream in the caspase cascade, receiving activation signals from both initiator caspases (caspase-8, -9, -10) and from other executioner caspases like caspase-3[@slee1999]. This creates amplification loops that ensure complete execution of apoptosis once the cascade is initiated.
Substrates and Cellular Functions
Activated caspase-7 cleaves numerous cellular substrates[@d_amours2001]:
DNA Repair Proteins
- PARP (Poly ADP-Ribose Polymerase): Cleavage inactivates PARP's DNA repair function, contributing to energy depletion in apoptotic cells
- DNA-PKcs: Cleavage disrupts DNA damage repair mechanisms
Structural Proteins
- Lamins: Cleavage leads to nuclear envelope breakdown
- Actin and Tubulin: Cleavage disrupts cytoskeletal integrity
Anti-Apoptotic Proteins
- BCL-2: Cleavage can inactivate its anti-apoptotic function
- MCL-1: Cleavage promotes apoptosis
Other Key Substrates
- GADPH: Cleavage contributes to energy collapse
- β-Catenin: Cleavage disrupts cell adhesion
- AIF: Cleavage can promote chromatin condensation
Role in Neurodegeneration
Alzheimer's Disease
Caspase-7 plays multiple critical roles in Alzheimer's disease pathogenesis:
Synaptic Loss: Caspase-7 activation contributes to synaptic dysfunction and loss in AD. The enzyme cleaves key synaptic proteins including PSD-95 and synaptophysin, leading to dendritic spine elimination and synaptic depression[@chen2020]. This mechanism may underlie the early cognitive decline observed in AD.
Tau Pathology: Caspase-7 cleaves tau protein at multiple sites, generating truncated tau fragments that have enhanced aggregation potential[@kim2020]. These cleavage products may contribute to the formation of neurofibrillary tangles and spread of tau pathology.
Amyloid-beta Toxicity: Aβ oligomers activate caspase-7, and the enzyme contributes to Aβ-induced neuronal death. Caspase-7 activation is elevated in AD brain tissue, particularly in regions with high amyloid burden[@onoufriou2007].
PARP Cleavage: Caspase-7 cleaves PARP in AD brain, leading to depletion of cellular energy reserves and accelerating neuronal death[@engidawork2021].
Parkinson's Disease
In Parkinson's disease, caspase-7 mediates dopaminergic neuron death:
MPTP Toxicity: Caspase-7 deficiency protects against MPTP-induced dopaminergic neuron loss in mouse models[@yang2018]. The enzyme is activated in the substantia nigra pars compacta following MPTP exposure.
Alpha-synuclein Toxicity: Caspase-7 is activated in response to alpha-synuclein aggregation and contributes to neurodegeneration in cellular and animal models of PD[@cheng2019]. The enzyme may cleave alpha-synuclein, generating fragments that accelerate aggregation.
Oxidative Stress: Mitochondrial dysfunction and oxidative stress in PD activate caspase-7 through both intrinsic and extrinsic pathways.
Amyotrophic Lateral Sclerosis (ALS)
Caspase-7 is elevated and activated in ALS:
Motor Neuron Death: Caspase-7 activation is observed in ALS motor neurons and contributes to selective motor neuron vulnerability[@choi2019]. The enzyme is activated in both sporadic and familial ALS cases.
Neuromuscular Junction Denervation: Caspase-7 mediates the process of neuromuscular junction denervation in ALS models through cleavage of postsynaptic proteins[@choi2016].
Excitotoxicity: Glutamate-induced excitotoxicity activates caspase-7 in motor neurons, contributing to the excitotoxic component of ALS pathogenesis.
Stroke and Traumatic Brain Injury
Ischemic Stroke: Following cerebral ischemia, caspase-7 is activated and contributes to delayed neuronal death in the penumbra region[@lin2021]. The enzyme is activated both directly by ischemia and indirectly through secondary mechanisms including excitotoxicity and inflammation.
Traumatic Brain Injury (TBI): Caspase-7 contributes to secondary brain injury following trauma through apoptosis of damaged neurons[@gonzalez2019]. Inhibition of caspase-7 has been shown to improve functional recovery in experimental TBI models.
Therapeutic Implications
Caspase Inhibitors as Neuroprotective Agents
Caspase-7 represents a promising therapeutic target for neurodegenerative diseases[@schlossarek2020]:
Peptide Inhibitors: Z-LEHD-FMK and similar selective inhibitors have shown neuroprotective effects in experimental models
Small Molecule Inhibitors: Development of brain-penetrant caspase-7 selective inhibitors is ongoing
Mitochondria-Targeted Inhibitors: Targeting inhibitors to mitochondria enhances neuroprotective effects
Gene Therapy Approaches: Using viral vectors to deliver caspase-7 inhibitory proteinsChallenges
Therapeutic targeting of caspase-7 faces several challenges:
- Pan-caspase inhibition may cause unacceptable side effects
- Apoptosis has important functions in normal cellular homeostasis
- Timing of intervention is critical—early intervention may be most effective
Expression Pattern
Brain Expression
Caspase-7 is expressed in multiple brain regions:
- Cerebral Cortex: High expression, particularly in layer 5 pyramidal neurons
- Hippocampus: Moderate expression in CA1-CA3 regions and dentate gyrus
- Cerebellum: Expression in Purkinje cells and granule cells
- Substantia Nigra: Expression in dopaminergic neurons
- Spinal Cord: Expression in motor neurons
Cell Type Expression
Caspase-7 is expressed in both neurons and glial cells:
- Neurons (pyramidal, GABAergic, dopaminergic)
- [Astrocytes](/cell-type- [Oligodendrocytes](/cell-types/oligodendrocytes)oglia
- [Oligodendrocytes](/cell-types/oligodendrocytes)
See Also
- [CASP3 Gene](/genes/casp3) - Related executioner caspase
- [CASP9 Gene](/genes/casp9) - Initiator caspase in intrinsic pathway
- [CASP8 Gene](/genes/casp8) - Initiator caspase in extrinsic pathway
- [Apoptosis Pathways](/mechanisms/apoptosis)
- [Alzheimer's Disease Mechanisms](/mechanisms/alzheimers-pathogenesis)
- [Parkinson's Disease Mechanisms](/mechanisms/parkinsons-pathogenesis)
- [PARP in Neurodegeneration](/mechanisms/parp-activation)