The Integrated Stress Response (ISR) is a central regulatory pathway that controls global protein synthesis through phosphorylation of eIF2α (Ser51). In ALS motor neurons, this hypothesis proposes that chronic ISR activation (via PERK, GCN2, HRI, or PKR pathways) caused by proteostatic stress (TDP-43/FUS aggregates), oxidative stress, and ER stress creates a pathological eIF2α~P state that represses axonal protein synthesis below the threshold required for synaptic maintenance and axonal repair, leading to progressive NMJ denervation.
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Curated pathway diagram from expert analysis
flowchart TD
A["Proteostatic and ER Stress
TDP43 FUS C9orf72 Burden"]
B["PERK GCN2 HRI PKR Sensors
Integrated Stress Response"]
C["EIF2S1 eIF2alpha Ser51 Phosphorylation
Translation Initiation Brake"]
D["Global Protein Synthesis Repression
Axonal mRNA Translation Drops"]
E["ATF4 ATF5 CHOP Program
Chronic Stress Transcription"]
F["Synaptic Maintenance Failure
Distal Axon Repair Deficit"]
G["ALS Motor Neuron Vulnerability
Denervation and Degeneration"]
A --> B
B --> C
C --> D
C --> E
D --> F
E --> G
F --> G
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
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No DepMap CRISPR Chronos data found for EIF2S1,eIF2α,PERK,GCN2,ATF4,ATF5,CHOP,DDIT3,integrated stress response,protein synthesis.
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