ATM (Ataxia Telangiectasia Mutated) is a DNA damage response (DDR) kinase that normally activates in response to double-strand breaks (DSBs). This hypothesis proposes that in ALS, chronic mitochondrial dysfunction and ROS overproduction cause persistent low-level ATM activation that exceeds the capacity of DNA repair machinery, leading to DDR overflow and pathological p53 activation that drives motor neuron apoptosis. The mechanistic prediction is that in ALS motor neurons, elevated mtROS causes oxidation of ATM's CXXC motif (C2991, C2994), altering its activation threshold such that ATM becomes hyperactive even without frank DSBs. Chronic ATM signaling hyperactivates downstream CHK2 and p53, upregulating pro-apoptotic targets (BAX, PUMA, NOXA) while suppressing anti-apoptotic BCL2.
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Curated pathway diagram from expert analysis
flowchart TD
A["Mitochondrial ROS
ALS Oxidative Stress"]
B["DNA Double Strand Breaks
Persistent Damage Signal"]
C["ATM Kinase Activation
DDR Overflow"]
D["CHEK2 Signal Relay
Checkpoint Amplification"]
E["TP53 Stabilization
PUMA BAX Induction"]
F["BCL2 Survival Buffer Exhausted
Mitochondrial Apoptosis"]
G["Motor Neuron Death
ALS Progression"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
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No clinical trials data available
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 ATM,CHEK2,TP53,BAX,PUMA,BCL2,DNA damage response,oxidative stress.
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