[^1]
[^2]
[^3]
[^4]
| Symbol | CASP6 |
| Full Name |
Caspase-6, Apoptosis-Related Cysteine Peptidase |
| Chromosome |
4q25 |
| NCBI Gene |
839 |
| Ensembl |
ENSG00000138794 |
| OMIM |
601532 |
| UniProt |
P55212 |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Huntington's Disease](/diseases/huntingtons), [ALS](/diseases/als) |
| Expression |
Brain (hippocampus, [cortex](/brain-regions/cortex), striatum), ubiquitous |
[Tau](/proteins/tau) (D421)
[Huntingtin](/proteins/huntingtin) (D586)
Lamin A/C
[APP](/entities/app-protein)
α-Tubulin |
CASP6 (Caspase-6) is a gene on chromosome 4q25 encoding an executioner cysteine-aspartate protease that plays a central role in neuronal apoptosis and neurodegeneration. Unlike other executioner caspases (CASP3, CASP7), caspase-6 has emerged as a uniquely neurodegeneration-relevant protease due to its ability to cleave critical neuronal substrates — most notably tau at Asp421 and huntingtin at Asp586 — and its early activation in Alzheimer's disease and Huntington's disease pathogenesis.
Key takeaway: Caspase-6 is the principal protease that cleaves tau at D421 in AD brains and huntingtin at D586 in HD brains. Its activation precedes overt neurodegeneration and is being pursued as a therapeutic target for multiple neurodegenerative diseases.
¶ Gene Structure and Expression
CASP6 spans approximately 15 kb on chromosome 4q25, comprising 7 exons. The gene encodes a 293-amino acid proenzyme (procaspase-6) that requires proteolytic activation. Alternative splicing generates CASP6α (full-length, catalytically active) and CASP6β (lacking exon 6, catalytically inactive, acts as dominant-negative inhibitor).
CASP6 is expressed broadly in the CNS with particular relevance in:
- Hippocampus: Strong expression in CA1 pyramidal neurons, the most vulnerable neurons in AD
- Entorhinal cortex: Activated caspase-6 is detected in the earliest Braak stages (I-II)
- Striatum: High expression in medium spiny neurons, relevant to Huntington's disease
- Cerebral cortex: Broad expression across cortical layers
- Substantia nigra: Moderate expression in dopaminergic neurons
Expression data is available from the Allen Human Brain Atlas.
CASP6 expression is regulated by:
- p53: DNA damage and cellular stress upregulate CASP6 transcription
- NF-κB: Inflammatory signaling can induce CASP6 expression
- Nerve growth factor deprivation: NGF withdrawal in sympathetic neurons upregulates CASP6
- Amyloid-β exposure: Aβ oligomers increase CASP6 expression and activation in neurons
Procaspase-6 (p34) is activated by proteolytic cleavage:
- Initiator caspase cleavage: Caspase-1 or caspase-3 cleave procaspase-6 at Asp179 and Asp193
- Self-activation: Uniquely among executioner caspases, procaspase-6 can undergo intramolecular self-cleavage at Asp179, enabling activation without upstream caspase signals
- Assembly: Active caspase-6 is a homodimer of p18/p11 subunits (large subunit: residues 24-179, small subunit: residues 194-293)
Caspase-6 cleaves multiple substrates critical for neuronal function:
- Tau at Asp421: Generates a truncated tau fragment (Tau-ΔC) that aggregates more readily, has increased toxicity, and is found in neurofibrillary tangles at the earliest disease stages
- Huntingtin at Asp586: Produces toxic N-terminal fragments that aggregate and are required for HD pathogenesis (mutant huntingtin resistant to D586 cleavage does not cause neurodegeneration in mice)
- APP at Asp664: Generates cytotoxic C-terminal APP fragment (C31) that induces apoptosis
- Lamin A/C: Nuclear envelope disruption, a hallmark of apoptotic cells
- α-Tubulin: Cytoskeletal breakdown and axonal degeneration
- Presenilin-1: Modulates γ-secretase complex activity
- VDAC1: Mitochondrial outer membrane permeabilization
Emerging evidence suggests caspase-6 has non-apoptotic roles in neurons:
- Axon pruning: Caspase-6 mediates developmental axon degeneration without triggering neuronal death
- Synaptic plasticity: Low-level caspase-6 activity modulates long-term depression (LTD)
- Neuroinflammation: Caspase-6 activates the NLRP3 inflammasome pathway
- B cell activation: Role in adaptive immunity
Caspase-6 plays a central and early role in AD:
- Early activation: Active caspase-6 immunoreactivity is detected in entorhinal cortex and hippocampus at Braak stages I-II, before clinical symptoms appear
- Tau cleavage: Caspase-6-cleaved tau (Tau-ΔC) is a major component of neurofibrillary tangles
- Neoepitope marker: Antibodies recognizing caspase-6-cleaved tau (TauC6) specifically label AD pathology
- Cognitive correlation: Levels of active caspase-6 in hippocampus correlate inversely with episodic and semantic memory performance in non-demented elderly
- Seeding enhancement: Caspase-6-cleaved tau has enhanced aggregation kinetics and promotes tau seeding
- APP cleavage: Caspase-6 generates toxic C31 fragment of APP, contributing to synaptic dysfunction
Caspase-6 is essential for HD pathogenesis:
- Cleavage of mutant huntingtin at Asp586 generates toxic N-terminal fragments
- Huntingtin resistant to caspase-6 cleavage (D586A mutation) prevents neurodegeneration in YAC128 HD mice
- Active caspase-6 is elevated in HD striatum before symptom onset
- Caspase-6 inhibition is neuroprotective in multiple HD models
In amyotrophic lateral sclerosis:
- Caspase-6 is activated in spinal cord motor neurons
- Cleaves neurofilament proteins, contributing to axonal degeneration
- Activated in response to mutant SOD1 toxicity
- Caspase-6 is rapidly activated after cerebral ischemia
- Contributes to delayed neuronal death in the penumbra
- Inhibition reduces infarct volume in animal models
| Age Group |
Caspase-6 Activity |
Significance |
| Young adult |
Low, basal |
Normal neuronal maintenance |
| Middle-aged |
Increasing |
Begins in entorhinal cortex |
| Elderly (cognitively normal) |
Moderate |
Correlates with subclinical cognitive decline |
| Mild AD |
High |
Spreads to hippocampus CA1 |
| Moderate-severe AD |
Very high |
Widespread cortical activation |
Active caspase-6 immunoreactivity closely follows Braak staging:
- Stage I-II: Entorhinal cortex (transentorhinal region)
- Stage III-IV: Hippocampus, temporal cortex
- Stage V-VI: Neocortical regions
This distribution parallels tau pathology spread and precedes frank neuronal loss.
- Z-VEID-FMK: Research tool peptidomimetic inhibitor; neuroprotective in cell and animal models
- Peptide-based inhibitors: VEID tetrapeptide derivatives with improved selectivity
- Small molecule inhibitors: Multiple pharmaceutical programs targeting caspase-6 active site
- Allosteric inhibitors: Compounds binding outside the active site to lock caspase-6 in an inactive conformation
- Zinc coordination: Zinc inhibits caspase-6 at physiological concentrations, suggesting metal homeostasis as a regulatory mechanism
- Upstream intervention: Blocking caspase-6 activation by inhibiting caspase-1 or caspase-3
- Substrate protection: Designing tau or huntingtin mutants resistant to caspase-6 cleavage (gene therapy approaches)
- Dominant-negative CASP6β: Overexpression of the inactive splice variant to compete with active caspase-6
- Anti-sense oligonucleotides: Reducing CASP6 expression