TBK1 Loss Locks Microglia in an Aged/Senescent Transcriptional State, Fueling ALS-Associated SASP
🧪 Overview
The hypothesis proposes that loss-of-function mutations in TBK1 contribute to ALS pathogenesis by trapping microglia in a senescent, pro-inflammatory state characterized by the Senescence-Associated Secretory Phenotype (SASP), thereby accelerating disease progression. Supporting evidence includes a 2025 Nat Commun study demonstrating that microglia-specific TBK1 deletion in an ALS/FTD mouse model reproduces an aged-like transcriptional signature with increased inflammatory gene expression. Complementary work published in Cell (2018) established that partial TBK1 insufficiency during aging unleashes RIPK1-driven inflammation, linking TBK1 haploinsufficiency to age-dependent neurodegeneration. Human genetic evidence further supports this axis: TBK1 haploinsufficiency is recognized as a causal familial ALS/FTD risk mechanism. Additionally, research published in Cell (2020) showed that TDP-43 pathology can activate cGAS-STING signaling in ALS, implicating the innate immune pathway downstream of TBK1 loss. However, contradictory evidence exists.
...🧬 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
🏥 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 → NF-κB / IRF3 / p62-autophagy / cGAS-STING 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 → NF-κB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF Cx3cr1-Cre;Tbk1fl/fl;SOD1G93A mice (microglia-specific TBK1 knockout in ALS model) are compared to littermate controls (SOD1G93A; Tbk1fl/fl), THEN microglial SA-β-gal+ cells and p16Ink4a/p21Cip1 ex | Increased microglial senescence markers (SA-β-gal activity, p16Ink4a/p21Cip1) and elevated SASP factor concentrations in CSF | — no observation — | pending | 0.45 |
| IF iPSC-derived microglia from ALS patients with TBK1 mutations (or TBK1 knockdown via CRISPRi) are compared to isogenic controls, THEN mRNA expression of senescent identity genes (CDKN2A, GLB1, LGALS | Upregulated senescence transcriptional signature and SASP secretome in patient-derived microglia with impaired TBK1 | — no observation — | pending | 0.50 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |