Shared mechanism across ALS, FTD, PD: TBK1 coordinates selective autophagy adaptors and innate immune tone. TBK1 haploinsufficiency causes ALS/FTD, while the same PINK1/Parkin/TBK1-adjacent mitochondrial quality-control network constrains PD-like mitochondrial and alpha-synuclein stress.
Falsifiable prediction: Partial TBK1 restoration should increase phospho-OPTN recruitment and reduce p62/TDP-43 aggregate load in ALS/FTD neurons; in PD dopaminergic neurons it should improve damaged-mitochondria clearance after rotenone by at least 20%.
Proposed experiment: Use TBK1 haploinsufficient ALS/FTD neurons and PD dopaminergic stress models; compare TBK1 rescue, kinase-dead TBK1, and vector controls; measure p-OPTN, p62, mitophagy flux, interferon/NF-kB markers, aggregate burden, and survival.
Cross-disease confidence rationale: Strong ALS/FTD genetics, with PD extrapolation through selective mitophagy network biology.
Internal SciDEX support: SciDEX support query found 29 matching hypotheses across 8 disease labels, including 29 with debate_count > 0.
Auto-built from this analysis's top knowledge-graph edges.
graph TD
TBK1["TBK1"] -->|cross disease mech| FTD["FTD"]
TBK1_1["TBK1"] -->|cross disease mech| PD["PD"]
h_cross_synth_tbk1_optn_a["h-cross-synth-tbk1-optn-autophagy"] -->|proposes shared me| TBK1_2["TBK1"]
TBK1_3["TBK1"] -->|cross disease mech| ALS["ALS"]
style TBK1 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style TBK1_1 fill:#4fc3f7,stroke:#333,color:#000
style PD fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_tbk1_optn_a fill:#4fc3f7,stroke:#333,color:#000
style TBK1_2 fill:#4fc3f7,stroke:#333,color:#000
style TBK1_3 fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000No curated PDB or AlphaFold mapping for TBK1 yet. Search RCSB →
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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Partial TBK1 restoration should increase phospho-OPTN recruitment and reduce p62/TDP-43 aggregate load in ALS/FTD neurons; in PD dopaminergic neurons it should improve damaged-mitochondria clearance a | If this mechanism is real, then Partial TBK1 restoration should increase phospho-OPTN recruitment and reduce p62/TDP-43 aggregate load in ALS/FTD neurons; in PD | — no observation — | pending | 0.73 |