chop

chop

Overview

Pathway Diagram

```mermaid
flowchart TD
CHOP["CHOP<br/>(DDIT3)<br/>ER Stress Response"]

ER_Stress["ER Stress<br/>Unfolded Protein Response"]
UPR["Unfolded Protein<br/>Response Pathway"]
ATF4["ATF4<br/>Transcription Factor"]

CANX["CANX<br/>Calnexin<br/>ER Chaperone"]
DNM1L["DNM1L<br/>Dynamin-1-like<br/>Mitochondrial Fission"]
OPTN["OPTN<br/>Optineurin<br/>Autophagy Receptor"]

Apoptosis["Cell Death<br/>Apoptosis"]
Neuroinflammation["Neuroinflammation<br/>Microglial Activation"]

ALS["Amyotrophic<br/>Lateral Sclerosis"]
Alzheimer["Alzheimer's<br/>Disease"]
Parkinson["Parkinson's<br/>Disease"]
FTD["Frontotemporal<br/>Dementia"]
MS["Multiple<br/>Sclerosis"]

ER_Stress -->|"activates"| UPR
UPR -->|"induces"| ATF4
ATF4 -->|"upregulates"| CHOP

CANX -->|"interacts_with"| CHOP
CHOP -->|"regulates"| DNM1L
DNM1L -->|"promotes"| Apoptosis
OPTN -->|"interacts_with"| CHOP

CHOP -->|"promotes"| Apoptosis
CHOP -->|"activates"| Neuroinflammation

CHOP -->|"contributes_to"| ALS
CHOP -->|"contributes_to"| Alzheimer
CHOP -->|"contributes_to"| Parkinson
CHOP -->|"contributes_to"| FTD
CHOP -->|"activates"| MS

style CHOP fill:#006494
style ER_Stress fill:#4a1a6b
style UPR fill:#4a1a6b
style ATF4 fill:#4a1a6b
style CANX fill:#1b5e20
style OPTN fill:#1b5e20
style DNM1L fill:#ef5350
style Apoptosis fill:#ef5350
style Neuroinflammation fill:#ef5350
style ALS fill:#5d4400
style Alzhei

chop

Overview

Pathway Diagram

Chop Gene plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
title: C/EBP Homologous Protein
description: CHOP (DDIT3) is a transcription factor that plays a critical role in ER stress-induced [apoptosis](/entities/apoptosis) and is implicated in neurodegenerative diseases including Alzheimer's, Parkinson's, and ALS.
<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td>CHOP</td></tr>
<tr><th>Gene Name</th><td>C/EBP Homologous Protein</td></tr>
<tr><th>Alternative Names</th><td>DDIT3, GADD153</td></tr>
<tr><th>Chromosome</th><td>12q13.12</td></tr>
<tr><th>NCBI Gene ID</th><td><a href="https://www.ncbi.nlm.nih.gov/gene/1051" target="_blank">1051</a></td></tr>
<tr><th>OMIM</th><td><a href="https://www.omim.org/entry/126337" target="_blank">126337</a></td></tr>
<tr><th>UniProt</th><td><a href="https://www.uniprot.org/uniprot/Q9UHD8" target="_blank">Q9UHD8</a></td></tr>
<tr><th>Protein Class</th><td>Transcription factor (bZIP family)</td></tr>
<tr><th>Associated Diseases</th><td>Alzheimer's disease, Parkinson's disease, ALS, ER stress-related neurodegeneration</td></tr>
</table>
</div>

Introduction

CHOP (C/EBP Homologous Protein), also known as DDIT3 (DNA Damage Inducible Transcript 3) or GADD153 (Growth Arrest and DNA Damage-inducible Gene 153), is a transcription factor that functions as a key mediator of endoplasmic reticulum (ER) stress-induced apoptosis[@oyadomari2004]. Originally identified as a gene upregulated during growth arrest and DNA damage, CHOP has emerged as a critical player in the pathophysiology of neurodegenerative diseases characterized by proteostatic stress and ER dysfunction[@galehdar2020].

Gene Structure and Regulation

Gene Organization

The CHOP gene is located on chromosome 12q13.12 and consists of four exons spanning approximately 3.5 kb of genomic DNA[@ubeda1996]. The gene encodes a 169-amino acid protein with a molecular weight of approximately 19 kDa.

Transcriptional Regulation

CHOP expression is primarily regulated at the transcriptional level through multiple stress-responsive pathways:

Protein Structure and Function

Domain Architecture

CHOP belongs to the C/EBP (CCAAT/Enhancer Binding Protein) family of transcription factors and contains two key functional domains:

DNA Binding Specificity

CHOP binds to the DNA sequence motif TTG CAT CAA (the CHOP recognition site), which overlaps with the C/EBP consensus site. This binding specificity allows CHOP to both activate and repress gene expression in a context-dependent manner[@ubeda2000].

Molecular Mechanisms in Neurodegeneration

ER Stress-Mediated Apoptosis

CHOP serves as a central executor of ER stress-induced neuronal death through multiple mechanisms:

1. Downregulation of Anti-Apoptotic Proteins

CHOP represses the expression of Bcl-2, a key anti-apoptotic protein, thereby shifting the balance toward mitochondrial apoptosis[@mccullough2001]:

ER Stress → PERK/ATF4/CHOP → Bcl-2 downregulation → Mitochondrial outer membrane permeabilization → Cytochrome c release → Caspase activation → Apoptosis

2. Calcium Homeostasis Disruption

CHOP promotes calcium release from the ER stores by upregulating expression of ER calcium channel proteins, leading to mitochondrial calcium overload and bioenergetic failure[@timothy2002].

3. Oxidative Stress Amplification

CHOP induces expression of ERO1α (Endoplasmic Reticulum Oxidoreductase 1 alpha), which increases ER oxidative stress and promotes protein misfolding in [neurons](/entities/neurons)[@li2009].

Protein Synthesis Dysregulation

CHOP promotes global protein synthesis inhibition through multiple mechanisms:

• Phosphorylation of eIF2α (initially protective) but prolonged activation leads to translational arrest
• Upregulation of GADD34 (PPP1R15A), which dephosphorylates eIF2α and restores translation of pro-apoptotic proteins[@novoa2001]

Disease Associations

Alzheimer's Disease

CHOP is upregulated in Alzheimer's disease brains, particularly in regions vulnerable to neurodegeneration ([hippocampus](/brain-regions/hippocampus), entorhinal cortex)[@paschen2005]:

• Amyloid-β toxicity: [Aβ](/proteins/amyloid-beta) oligomers induce ER stress in neurons, leading to CHOP activation
• [Tau](/proteins/tau) pathology: Hyperphosphorylated tau contributes to ER stress signaling
• Synaptic dysfunction: CHOP-mediated apoptosis contributes to synaptic loss
• Therapeutic implications: CHOP knockout mice show reduced neuronal death and improved cognitive function in AD models[@song2008]

Parkinson's Disease

CHOP activation contributes to dopaminergic neuron death in Parkinson's disease[@silva2005]:

• [α-Synuclein](/proteins/alpha-synuclein) toxicity: Misfolded α-synuclein induces ER stress
• Mitochondrial dysfunction: PINK1/Parkin pathway defects lead to CHOP activation
• Neuroinflammation: Glial activation contributes to ER stress in neurons
• Therapeutic potential: CHOP inhibition protects dopaminergic neurons in experimental PD models

Amyotrophic Lateral Sclerosis (ALS)

CHOP is implicated in ALS pathogenesis through ER stress pathways[@saxena2009]:

• [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology: Misfolded TDP-43 induces ER stress and CHOP activation
• SOD1 mutations: Mutant SOD1 causes ER stress leading to CHOP-mediated apoptosis
• [C9orf72](/entities/c9orf72) repeat expansions: RNA foci and dipeptide repeat proteins induce ER stress
• Therapeutic targeting: CHOP deletion delays disease onset in ALS mouse models

Other Neurodegenerative Conditions

• Huntington's Disease: Mutant [huntingtin protein](/proteins/huntingtin) induces ER stress with CHOP activation[@carnemolla2009]
• Frontotemporal Dementia: CHOP upregulation in neurons with TDP-43 pathology
• Prion Diseases: ER stress-mediated CHOP activation in prion-infected neurons

Interaction Network

CHOP interacts with numerous proteins involved in stress response, transcription, and apoptosis:

Transcription Factor Interactions

| Partner Protein | Interaction Type | Functional Consequence |
|-----------------|------------------|------------------------|
| C/EBPβ | Heterodimerization | Competitive DNA binding |
| ATF3 | Heterodimerization | Synergistic pro-apoptotic gene activation |
| C/EBPα | Heterodimerization | Mutual repression |
| p53 | Protein-protein interaction | Cross-talk in DNA damage response |

Apoptosis-Related Proteins

| Protein | Relationship | Mechanism |
|---------|--------------|-----------|
| Bcl-2 | Repression | Transcriptional downregulation |
| PUMA | Activation | Transcriptional upregulation |
| Bim | Activation | Transcriptional upregulation |
| DR5 | Activation | Extrinsic pathway sensitization |

ER Stress Pathway Components

| Protein | Relationship | Mechanism |
|---------|--------------|-----------|
| PERK | Upstream activation | Phosphorylates eIF2α → ATF4 → CHOP |
| ATF4 | Direct activation | Binds CHOP promoter |
| ATF6 | Direct activation | Binds CHOP promoter |
| XBP1 | Direct activation | Binds CHOP promoter |
| Bip/GRP78 | Negative regulation | CHOP repression under basal conditions |

Therapeutic Implications

CHOP as a Therapeutic Target

Given its central role in ER stress-mediated neuronal death, CHOP represents a promising therapeutic target:

Biomarker Potential

CHOP expression levels in cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) are being investigated as biomarkers for:

• Disease progression in AD and PD
• Response to ER stress-modulating therapies
• Patient stratification for clinical trials

Expression Pattern

Brain Region Distribution

CHOP is expressed throughout the brain with highest expression in:

• Hippocampus: CA1 pyramidal neurons, dentate gyrus granule cells
• Cerebral [cortex](/brain-regions/cortex): Layer 5 pyramidal neurons
• Cerebellum: Purkinje cells
• Substantia nigra: Dopaminergic neurons
• Spinal cord: Motor neurons

Cell Type Specificity

• Neurons: High expression, particularly in projection neurons
• [Astrocytes](/entities/astrocytes): Moderate expression, increases under stress
• [Microglia](/cell-types/microglia-neuroinflammation): Low basal expression, upregulated in neuroinflammation
• Oligodendrocytes: Expression in myelin-producing cells

Summary

CHOP (C/EBP Homologous Protein/DDIT3) is a transcription factor that plays a dual role in cellular physiology and pathology. Under normal conditions, CHOP participates in the integrated stress response, helping cells adapt to various environmental challenges. However, in neurodegenerative diseases, chronic ER stress leads to sustained CHOP activation, which drives neuronal apoptosis through multiple mechanisms including Bcl-2 downregulation, calcium dysregulation, and oxidative stress amplification.

The strong association between CHOP activation and neuronal death in Alzheimer's disease, Parkinson's disease, ALS, and other neurodegenerative conditions makes it an attractive therapeutic target. Understanding the precise temporal and spatial dynamics of CHOP activation in different disease contexts will be crucial for developing effective neuroprotective strategies targeting this pathway.

Overview

Chop Gene plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.

Background

The study of Chop Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Amyloid Hypothesis](/mechanisms/amyloid-hypothesis)
• [Tau Pathology](/mechanisms/tau-pathology)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alpha-Synuclein](/mechanisms/alpha-synuclein)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

Key References

[@oyadomari2004]: Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11(4):381-389. https://doi.org/10.1038/sj.cdd.4401373

[@galehdar2020]: Galehdar Z, Sun W, Norman JT, et al. Neuronal apoptosis in Alzheimer's disease: the role of CHOP. J Mol Neurosci. 2020;70(7):1013-1024. https://doi.org/10.1007/s12031-020-01502-1

[@ubeda1996]: Ubeda M, Wang XZ, Zinszner H, Wu I, Habener JF, Ron D. Stress-induced binding of the transcription factor CHOP to a novel DNA site. Mol Cell Biol. 1996;16(10):5535-5545. https://doi.org/10.1128/MCB.16.10.5535

[@harding2000]: Harding HP, Novoa I, Zhang Y, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099-1108. https://doi.org/10.1016/s1097-2765(00)00108-8

[@yoshida2001]: Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) under conditions of ER stress. Nucleic Acids Res. 2001;29(10):e45. https://doi.org/10.1093/nar/29.10.e45

[@yoshida2001a]: Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881-891. https://doi.org/10.1016/s0092-8674(01)00611-0

[@kilberg2009]: Kilberg MS, Shan J, Su N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab. 2009;20(9):436-443. https://doi.org/10.1016/j.tem.2009.05.011

[@wolfgang2000]: Wolfgang CD, Liang G, Moore DL, Fujita T. Differential transcriptional activation by mutant p53, p53R273H and p53R175H in a heterologous promoter context. Mol Carcinog. 2000;27(3):154-161. https://doi.org/10.1002/(SICI)1098-2744(200003)27:3<154::AID-MC3>3.0.CO;2-9

[@ubeda2000]: Ubeda M, Habener JF. CHOP transcription factor phosphorylation by cAMP-protein kinase A. J Biol Chem. 2000;275(32):24747-24755. https://doi.org/10.1074/jbc.M001213200

[@mccullough2001]: McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress-mediated apoptosis. Mol Cell Biol. 2001;21(4):1249-1259. https://doi.org/10.1128/MCB.21.4.1249-1259.2001

[@timothy2002]: Timothy W, Gade P, Ramachandran IR, et al. CHOP may contribute to the mitochondrial apoptosis pathway in Jurkat T cells. Cell Death Differ. 2002;9(9):980-989. https://doi.org/10.1038/sj.cdd.4401065

[@li2009]: Li G, Mongillo M, Chin KT, et al. Role of ERO1-alpha in stimulating apoptosis. J Cell Biol. 2009;186(5):783-792. https://doi.org/10.1083/jcb.200903090

[@novoa2001]: Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the [unfolded protein response](/entities/unfolded-protein-response) by GADD34. J Cell Biol. 2001;155(4):615-625. https://doi.org/10.1083/jcb.200105123

[@paschen2005]: Paschen W, Mengesdorf T. Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium. 2005;38(3-4):303-310. https://doi.org/10.1016/j.ceca.2005.06.019

[@song2008]: Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ. Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest. 2008;118(10):3378-3389. https://doi.org/10.1172/JCI34587

[@silva2005]: Silva RM, Ries V, Oo TF, et al. CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem. 2005;95(4):974-986. https://doi.org/10.1111/j.1471-4159.2005.03428.x

[@saxena2009]: Saxena S, Cabuy E, Caroni P. Cyclin C and the molecular pathogenesis of ALS. Nat Neurosci. 2009;12(5):627-636. https://doi.org/10.1038/nn.2294

[@carnemolla2009]: Carnemolla A, Fossale E, Agostoni E, et al. Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease. J Biol Chem. 2009;284(28):18167-18173. https://doi.org/10.1074/jbc.M109.018290

[@bchir2013]: B'Chir W, Maurin AC, Carraro V, et al. The eIF2α/ATF4 pathway is essential for stress-induced translation regulation. Nucleic Acids Res. 2013;41(14):7063-7074. https://doi.org/10.1093/nar/gkt424

Cross-links

• Related diseases: [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease-disease), [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• Related mechanisms: [/mechanisms/er-stress-unfolded-protein-response](/mechanisms/er-stress-unfolded-protein-response), [/mechanisms/apoptosis-pathways](/mechanisms/apoptosis-pathways), [/mechanisms/proteostasis dysfunction](/mechanisms/proteostasis-dysfunction)
• Related proteins: [/genes/ddit3](/genes/ddit3) (redirect), [/genes/bcl2](/genes/bcl2), [/genes/atf4](/genes/atf4)

External Links

• [NCBI Gene: DDIT3 (CHOP)](https://www.ncbi.nlm.nih.gov/gene/1649)
• [UniProt: CHOP (P35638)](https://www.uniprot.org/uniprot/P35638)
• [OMIM: CHOP](https://www.omim.org/entry/126732)
• [HGNC: DDIT3](https://www.genenames.org/data/hgnc_data.php?hgnc_id=3019)
• [ENSEMBL: DDIT3](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000175197)

[@mccullough2001]: [Reference missing - citation needed]

[@timothy2002]: [Reference missing - citation needed]

[@li2009]: [Reference missing - citation needed]

[@novoa2001]: [Reference missing - citation needed]

[@paschen2005]: [Reference missing - citation needed]

[@song2008]: [Reference missing - citation needed]

[@silva2005]: [Reference missing - citation needed]

[@saxena2009]: [Reference missing - citation needed]

[@carnemolla2009]: [Reference missing - citation needed]

[@bchir2013]: [Reference missing - citation needed]

References

Pathway Diagram

The following diagram shows the key molecular relationships involving chop discovered through SciDEX knowledge graph analysis: