Caspase 2 is a protein that caspase 2 has diverse cellular functions beyond [apoptosis](/entities/apoptosis):. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@troy2014]
[@zhang2015]
Structure
Caspase 2 is an evolutionarily conserved caspase with unique features:
Prodomain: Long N-terminal prodomain (~165 aa) containing a CARD (Caspase Recruitment Domain)
Large subunit (p19): ~19 kDa catalytic subdomain
Small subunit (p12): ~12 kDa subunit
Active heterotetramer: p19₂p12₂ forms the active enzyme
Caspase 2 is the most conserved caspase across species and is unique among caspases in its ability to be activated by multiple mechanisms.
Normal Function
Caspase 2 has diverse cellular functions beyond apoptosis:
Cell Death Regulation
Apoptosis initiation: Can initiate apoptosis independently or through the apoptosome
PIDDosome activation: Forms the PIDDosome complex for caspase-2 activation
Mitochondrial pathway: Responds to mitochondrial outer membrane permeabilization
DNA Repair and Genome Stability
p53 activation: Cooperates with p53 in DNA damage response
Checkpoint regulation: Links DNA damage to apoptosis
Tumor suppression: Acts as a tumor suppressor
Cellular Homeostasis
Metabolic regulation: Affects cellular metabolism
Endoplasmic reticulum stress: Responds to ER stress
Pyroptosis: Can mediate inflammasome-independent pyroptosis
Role in Neurodegeneration
Huntington's Disease
Caspase 2 plays a critical role in HD pathogenesis:
[Troy et al., A nonapoptotic role for CASP2/caspase 2: modulation of autophagy (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24879153/)
[Sutton et al., Caspase-2 cleavage of tau reversibly impairs memory (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27723722/)
[Zhao et al., Caspase-2 mRNA levels in Alzheimer's disease and Lewy Body dementia (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/36129947/)
[C CURRENT et al., Caspase-2 inhibition protects dorsal root ganglion neurons from apoptosis (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23451279/)
[Ahmed et al., Combined suppression of CASP2 and CASP6 protects retinal ganglion cells (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24727569/)
[Blomgren et al., Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22237207/)
[Mahoney et al., Caspase-2 in neuronal apoptosis and neurodegeneration (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18633446/)
[O'Reilly et al., Caspase-2: The orphan caspase (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19158484/)
[Krumschnabel et al., Apoptotic and non-apoptotic functions of caspase-2 (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19373253/)
[Zhang et al., Caspase-2 deficiency promotes autophagy in neuroprotection (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26051187/)
Pathway Diagram
The following diagram shows the key molecular relationships involving Caspase 2 (CASP2) discovered through SciDEX knowledge graph analysis: