Caspase-7 is an executioner caspase in the caspase family of cysteine proteases that plays a central role in programmed cell death (apoptosis). It is one of the key effector caspases that executes the apoptotic program by cleaving a broad range of cellular substrates. In neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), caspase-7 activation contributes to neuronal loss through both apoptosis and non-apoptotic functions. Understanding caspase-7's role in neurodegeneration is crucial for developing therapeutic strategies targeting cell death pathways.
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Gene: [CASP7](/genes/casp7)
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UniProt ID: [P55210](https://www.uniprot.org/uniprot/P55210)
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PDB Structure: 1F1J, 1I51, 3KAI, 4JJE
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Molecular Weight: ~35 kDa (pro-caspase), ~20 kDa (active form)
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Subcellular Localization: Cytoplasm, cytoskeleton
Protein Family: Caspase family, peptidase C14 family
Caspase-7 is synthesized as a zymogen (pro-caspase-7) that requires activation:
- Pro-domain: Contains a short N-terminal prodomain (~23 amino acids)
- Large subunit (p20): Contains the catalytic cysteine residue
- Small subunit (p12): Completes the active site formation
- Active form: The heterotetrameric active caspase-7 consists of two p20/p12 heterodimers
- Catalytic dyad: His237 and Cys277 form the catalytic dyad essential for protease activity
- Substrate-binding pocket: Recognizes the DEVD tetrapeptide sequence (caspase-7 preferred cleavage site)
Crystal structures of active caspase-7 (PDB: 1F1J, 3KAI) have revealed the dimeric architecture and substrate-binding mechanisms.
In healthy cells, caspase-7 participates in several important processes:
- Apoptosis execution: Caspase-7 is activated by initiator caspases (caspase-8, caspase-9 via proteolytic cleavage
- Substrate cleavage: Cleaves structural proteins (lamins, gelsolin), repair enzymes (PARP), and signaling molecules
- Cell disassembly: Facilitates cellular dismantling during programmed cell death
- Development: Essential for normal embryonic development (caspase-7 knockout mice are viable but show defects)
- Immune regulation: Participates in immune cell homeostasis and cytokine processing
Caspase-7 is activated in AD brains and contributes to neuronal death:
- Amyloid-beta toxicity: Aβ exposure triggers caspase-7 activation in neurons
- Tau cleavage: Caspase-7 cleaves tau protein, generating toxic fragments that may propagate pathology
- Synaptic loss: Caspase-7 activation leads to synaptic protein degradation
- PARP cleavage: Excessive caspase-7 activation causes PARP cleavage, leading to energy depletion and cell death
In PD, caspase-7 mediates dopaminergic neuron loss:
- Mitochondrial dysfunction: Mitochondrial toxins activate caspase-7
- Alpha-synuclein toxicity: Caspase-7 is activated by alpha-synuclein aggregates
- Neuroinflammation: Glial activation triggers caspase-7 in neighboring neurons
Caspase-7 contributes to motor neuron degeneration in ALS:
- Mutant SOD1 toxicity: Caspase-7 is activated in ALS models with mutant SOD1
- Excitotoxicity: Glutamate excitotoxicity triggers caspase-7 activation
- Axonal degeneration: Caspase-7 mediates axonal breakdown
¶ Stroke and Traumatic Brain Injury
Caspase-7 activation following ischemia or trauma contributes to secondary neuronal damage.
Caspase-7 is a therapeutic target for neurodegenerative diseases:
- Caspase inhibitors: Pan-caspase and caspase-7-selective inhibitors have been developed
- Neuroprotective strategies: Targeting upstream activators to prevent caspase-7 activation
- Peptide-based inhibitors: DEVD-based peptides can block caspase-7 activity
- Challenges: Broad caspase inhibition affects vital cellular functions
- Wei et al., Caspase structure and function (2003)
- Miller et al., Caspase-7 cleavage in Alzheimer's disease (2000)
- Burguillos et al., Caspase signalling controls microglia activation (2011)
- LeBlanc, Caspase-6 in neurodegeneration (2003)
- Gao et al., Caspase-7 activation in Parkinson's disease (2005)