The Integrated Stress Response (ISR) controls cellular protein synthesis through eIF2α phosphorylation, but this hypothesis proposes that chronic ISR activation in ALS motor neurons creates a pathological cascade that specifically disrupts mitochondrial protein homeostasis and bioenergetics. In ALS, chronic eIF2α~P elevation (>0.7 normalized phosphorylation) caused by proteostatic stress from TDP-43/FUS aggregates selectively impairs synthesis of nuclear-encoded mitochondrial proteins, including Complex I subunits (NDUFS1, NDUFS3), Complex IV subunits (COX4I1, COX5A), and mitochondrial import machinery components (TOMM20, TIMM23).
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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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Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
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No DepMap CRISPR Chronos data found for EIF2S1,eIF2α,PERK,GCN2,ATF4,TOMM20,TIMM23,NDUFS1,NDUFS3,COX4I1,COX5A,mitochondrial protein import.
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