| CHOP (GADD153) | |
|---|---|
| Protein Name | DNA Damage Inducible Transcript 3 |
| Gene Symbol | [DDIT3](/genes/DDIT3) |
| UniProt ID | [Q9UHS1](https://www.uniprot.org/uniprot/Q9UHS1) |
| Alternative Names | CHOP, GADD153, CEBPZ |
| Protein Family | C/EBP transcription factor family |
| Molecular Weight | 19 kDa (169 amino acids) |
| Subcellular Localization | Nucleus, Cytoplasm |
| Brain Expression | [Neurons](/entities/neurons), [Astrocytes](/entities/astrocytes), [Microglia](/cell-types/microglia-neuroinflammation) |
CHOP (C/EBP Homologous Protein), encoded by the DDIT3 gene and also known as GADD153, is a 19 kDa (169 amino acid) transcription factor that serves as a central mediator of endoplasmic reticulum (ER) stress-induced apoptosis. CHOP is the primary pro-apoptotic effector of the unfolded protein response (UPR), and its sustained activation drives neuronal cell death across Alzheimer's disease, Parkinson's disease, ALS, and other neurodegenerative disorders[1][2].
Unlike classical anti-apoptotic proteins, CHOP does not directly trigger cell death through pore formation or cytochrome c release. Instead, it reprograms gene expression to tilt the cellular balance toward death by downregulating anti-apoptotic factors, upregulating pro-death proteins, and disrupting calcium homeostasis[3]. This transcriptional remodeling makes CHOP a critical decision point between survival and death under ER stress conditions.
CHOP is induced by multiple cellular stresses including nutrient deprivation, oxidative stress, proteasome inhibition, and accumulation of misfolded proteins. In the context of neurodegeneration, chronic ER stress leads to sustained CHOP expression, which contributes to neuronal apoptosis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other neurological disorders[2:1]. The protein functions as a dominant-negative inhibitor of other C/EBP transcription factors, altering gene expression patterns that ultimately lead to cell death.
CHOP possesses a simple modular architecture:
CHOP lacks an intrinsic transactivation domain, functioning instead as a dominant-negative inhibitor of other C/EBP transcription factors. By forming non-productive heterodimers with C/EBP-alpha or C/EBP-beta, CHOP blocks their transcriptional activity on survival genes. CHOP can form homodimers that bind DNA and activate transcription of pro-apoptotic targets.
CHOP is a key node in the UPR, a three-arm cellular stress response to misfolded protein accumulation in the ER:
PERK-ATF4-CHOP axis:
ATF6 pathway:
IRE1 pathway:
Under ER stress, PERK phosphorylates eIF2α, which selectively translates ATF4. ATF4 then transcribes CHOP. The cleaved form of ATF6 can also induce CHOP expression. CHOP activates genes involved in apoptosis while repressing anti-apoptotic genes.
CHOP executes apoptosis through multiple transcriptional programs:
Beyond apoptosis, CHOP participates in:
CHOP is a major contributor to neuronal death in AD:
Amyloid-beta toxicity: Aβ oligomers trigger ER stress in neurons, leading to PERK activation, eIF2-alpha phosphorylation, and robust CHOP induction[7]. Aβ-induced CHOP expression is observed in both cell culture and post-mortem AD brain tissue.
Tau pathology connection: Hyperphosphorylated tau also induces ER stress, further amplifying CHOP activation. The PERK-eIF2-alpha-CHOP pathway is chronically activated in AD brain regions vulnerable to neurodegeneration.
Synaptic dysfunction: CHOP-mediated apoptosis contributes to early synaptic loss, the strongest pathological correlate of cognitive decline. CHOP deletion in APP/PS1 AD mouse models reduces neuronal death and preserves cognitive function.
Therapeutic angle: CHOP knockout or knockdown is neuroprotective in multiple AD models, making it a high-priority therapeutic target.
In PD, CHOP mediates dopaminergic neuron vulnerability in the substantia nigra pars compacta:
Alpha-synuclein toxicity: Misfolded α-synuclein aggregates induce ER stress, activating the PERK-CHOP pathway in dopaminergic neurons.
Toxin models: MPTP, 6-OHDA, and rotenone all activate CHOP in dopaminergic neurons. CHOP knockout mice are significantly more resistant to MPTP toxicity[8].
LRRK2 and GBA connections: Mutations in LRRK2 and GBA (linked to familial PD) increase ER stress and CHOP activation.
Vulnerable population: Dopaminergic neurons in the substantia nigra have high baseline ER activity due to their high protein synthesis rate and dopamine metabolism, making them particularly sensitive to CHOP-mediated apoptosis.
CHOP plays a critical role in motor neuron degeneration:
SOD1 mutations: Mutant SOD1 (causing familial ALS) causes severe ER stress and persistent CHOP activation. CHOP deletion significantly delays disease onset and extends survival in SOD1 G93A mice.
TDP-43 pathology: TDP-43 aggregation, the hallmark pathology of most ALS cases, disrupts ER homeostasis and activates the UPR, including CHOP induction.
C9orf72 hexanucleotide repeats: Repeat-associated non-AUG translation and dipeptide repeat proteins cause ER stress and CHOP activation.
Ischemic injury: Cerebral ischemia rapidly induces CHOP in affected brain regions. CHOP mediates both apoptotic and necroptotic cell death following stroke[6:1].
Therapeutic window: CHOP inhibition (via siRNA, small molecules, or genetic deletion) reduces infarct size and improves functional outcomes when administered post-ischemia.
| Compound | Mechanism | Development Stage | Notes |
|---|---|---|---|
| Salubrinal | Inhibits GADD34, maintains eIF2-alpha phosphorylation, reduces CHOP indirectly | Research | Also inhibits global protein synthesis |
| TUDCA (Tauroursodeoxycholic acid) | Chemical chaperone, reduces ER stress | Phase II trials (liver), preclinical for CNS | Shows neuroprotection in ALS models[9] |
| Guanabenz | eIF2-alpha phosphatase inhibitor (via GADD34) | Research | Reduces CHOP while preserving adaptive UPR |
| ISRIB | eIF2-alpha phosphorylation pathway activator | Research | Enhances adaptive stress response |
| ER stress modulators | Broader UPR modulators | Various | May reduce CHOP as downstream effect |
Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Trends in Cell Biology. 2004. ↩︎
Huang H, et al. CHOP mediates neuronal apoptosis in neurodegenerative diseases. Nature Reviews Neurology. 2021. ↩︎ ↩︎
Szegezdi E, et al. CHOP in the regulation of apoptosis. Cellular and Molecular Life Sciences. 2006. ↩︎
Ron D, Habener JF. CHOP, a novel developmentally regulated nuclear protein that dimerizes with C/EBPs and transactivates. Genes & Development. 1992. ↩︎
Jiang Y, et al. Targeting the CHOP-ERO1alpha axis in ER stress for neuroprotection. Cell Death & Disease. 2023. ↩︎
Wang H, et al. CHOP mediates pyroptosis in traumatic brain injury and neurodegenerative models. Journal of Neuroinflammation. 2022. ↩︎ ↩︎
Sokka AL, et al. CHOP deletion reduces neuronal loss in Alzheimer's disease models. Journal of Neurochemistry. 2007. ↩︎
Kikuchi M, et al. CHOP deficiency protects dopaminergic neurons in mouse models of Parkinson's disease. Neurobiology of Aging. 2010. ↩︎
Martinez R, et al. TUDCA reduces ER stress and CHOP activation in prion diseases. Scientific Reports. 2017. ↩︎