¶ GADD34 (Growth Arrest and DNA Damage Inducible Protein 34)
GADD34 is a protein that 1. ER Stress Response: GADD34 is a key mediator of the integrated stress response (ISR). This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
GADD34 (DNAJC10,PPP1R15A) is a stress-inducible protein that promotes protein synthesis recovery after endoplasmic reticulum (ER) stress. It is involved in the unfolded protein response (UPR) and has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
GADD34 is a modular protein with distinct functional domains.
| Property |
Value |
| Gene |
PPP1R15A (also called GADD34) |
| UniProt |
Q9ZVB0 (mouse) / O43471 (human) |
| Molecular Weight |
~81 kDa (674 amino acids human) |
| Subcellular Localization |
Cytoplasm, ER membrane |
| Expression |
Low in normal cells; induced by stress |
- ER Stress Response: GADD34 is a key mediator of the integrated stress response (ISR)
- eIF2α Phosphatase: Forms a complex with PP1 to dephosphorylate eIF2α
- Protein Synthesis Recovery: Promotes translation recovery after stress resolution
- Pro-apoptotic Function: Facilitates cell death under prolonged ER stress
- C9orf72 Models: GADD34 elevated in C9orf72-associated ALS
- ER Stress: Critical contributor to ER stress in motor neurons
- Therapeutic Target: GADD34 inhibition may protect motor neurons
- SOD1 Models: GADD34 upregulated in SOD1 mutant mice
- Amyloid Toxicity: GADD34 induced by Aβ exposure
- Tau Pathology: Associated with ER stress in tauopathies
- Synaptic Dysfunction: Contributes to protein synthesis deficits
- Alpha-Synuclein: GADD34 response to α-syn toxicity
- ER Stress: Common pathway in PD pathogenesis
- Dopaminergic Neurons: Particularly vulnerable to GADD34 dysregulation
| Approach |
Status |
Notes |
| Small molecule inhibitors |
Preclinical |
Guanabenz derivatives |
| Antisense oligonucleotides |
Research |
ASOs targeting PPP1R15A |
| Gene therapy |
Research |
Viral delivery of dominant negatives |
- Motor Neuron Protection: GADD34 inhibition extends survival in ALS models
- Reduced ER Stress: Lower pro-apoptotic signaling
- Improved Protein Homeostasis: Better handling of misfolded proteins