TBK1 Deficiency Disrupts Microglial Metabolic Reprogramming, Promoting Glycolytic SASP in ALS
🧪 Overview
TBK1 loss-of-function mutations in ALS disrupt microglial metabolic homeostasis by impairing mTOR-dependent metabolic checkpoint signaling and mitochondrial quality control. Under normal conditions, TBK1 phosphorylates ULK1 and AMPK to coordinate autophagy-mediated mitochondrial turnover with oxidative metabolism, enabling microglia to maintain anti-inflammatory M2 polarization. In ALS patients with TBK1 mutations, defective mitophagy leads to accumulation of damaged mitochondria and compensatory upregulation of glycolysis through HIF-1α stabilization. This metabolic shift toward aerobic glycolysis (Warburg-like metabolism) fundamentally reprograms microglial transcriptional landscapes, favoring pro-inflammatory M1 polarization and sustained SASP production. The metabolic dysfunction creates a feed-forward loop where impaired oxidative phosphorylation increases ROS production from dysfunctional mitochondria, further activating HIF-1α and perpetuating glycolytic dependence.
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["dsDNA/dsRNA or Bacteria<br/>STING/MAVS Signal"]
B["TBK1 Activation<br/>IKK-epsilon Complex"]
C["IRF3 Phosphorylation<br/>Ser396 by TBK1"]
D["IRF3 Dimerization<br/>Nuclear Import"]
E["Type-I IFN Expression<br/>IFN-beta/IFN-alpha"]
F["Antiviral Defense<br/>ISG Upregulation"]
G["TBK1 Loss-of-Function<br/>ALS10 Mutations"]
H["OPTN/p62 Phosphorylation<br/>Selective Autophagy"]
A --> B
B --> C
B --> H
C --> D
D --> E
E --> F
G -.->|"impairs"| B
G -.->|"impairs"| H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#81c784,color:#81c784
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TBK1
No curated PDB or AlphaFold mapping for TBK1 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TBK1 → mTOR / ULK1 / AMPK / HIF-1α axis from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TBK1 → mTOR.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🏆 Arenas / Elo
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💾 Resource Usage
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |