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 (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](/entities/unfolded-protein-response) (UPR) and has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
Structure
GADD34 is a modular protein with distinct functional domains.
Normal Function
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
Role in Neurodegeneration
Amyotrophic Lateral Sclerosis (ALS)
[C9orf72](/entities/c9orf72) Models: GADD34 elevated in C9orf72-associated ALS
ER Stress: Critical contributor to ER stress in motor [neurons](/entities/neurons)
Therapeutic Target: GADD34 inhibition may protect motor neurons
SOD1 Models: GADD34 upregulated in SOD1 mutant mice
Alzheimer's Disease
Amyloid Toxicity: GADD34 induced by [Aβ](/proteins/amyloid-beta) exposure
[Tau](/proteins/tau) Pathology: Associated with ER stress in tauopathies
Synaptic Dysfunction: Contributes to protein synthesis deficits
Parkinson's Disease
[Alpha-Synuclein](/proteins/alpha-synuclein): GADD34 response to α-syn toxicity
ER Stress: Common pathway in PD pathogenesis
Dopaminergic Neurons: Particularly vulnerable to GADD34 dysregulation
Therapeutic Targeting
Inhibition Strategies
Protective Effects
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
Key Publications
[@novoa2003]: Novoa I, Zhang Y, Zeng H, et al. [Stress-induced gene expression requires programmed recovery from translational repression](https://pubmed.ncbi.nlm.nih.gov/14561789/). EMBO J. 2003;22(5):1180-1187.
[@saxena2009]: Saxena S, Cabuy E, Caroni P. [Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation after neuronal activation](https://pubmed.ncbi.nlm.nih.gov/19279218/). Nat Neurosci. 2009;12(5):589-591.
[@kim2014]: Kim HJ, Raphael AR, LaDow ES, et al. [Therapeutic modulation of eIF2α phosphorylation rescues stress-induced toxicity in a Drosophila model of TDP-43 proteinopathy](https://pubmed.ncbi.nlm.nih.gov/24439381/). Hum Mol Genet. 2014;23(18):4948-4958.
[Novoa I, Zhang Y, Zeng H, et al, Stress-induced gene expression requires programmed recovery from translational repression (2003)](https://pubmed.ncbi.nlm.nih.gov/14561789/)
[Saxena S, Cabuy E, Caroni P, Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation after neuronal activation (2009)](https://pubmed.ncbi.nlm.nih.gov/19279218/)
[Kim HJ, Raphael AR, LaDow ES, et al, Therapeutic modulation of eIF2α phosphorylation rescues stress-induced toxicity in a Drosophila model of TDP-43 proteinopathy (2014)](https://pubmed.ncbi.nlm.nih.gov/24439381/)