Impaired autophagic flux and lysosomal degradation capacity represents a convergent failure point across AD, PD, ALS, and FTD. Multiple druggable nodes exist: TFEB activation, GBA1 enhancement, TMEM175 modulation, and VPS35/retromer stabilization. Cross-disease genetic evidence (GBA1, VPS35, TMEM175, SORL1) and postmortem tissue validation support this mechanism. Best near-term path is biomarker-enriched trials in GBA1-PD or prodromal carriers. CNS druggability remains the primary development barrier.
Auto-built from this analysis's top knowledge-graph edges.
graph TD
GBA1_mutations["GBA1 mutations"] -->|increases risk| PD["PD"]
TREM2_R47H_variant["TREM2 R47H variant"] -->|increases risk| Ad["Ad"]
alpha_synuclein_fibrils["alpha-synuclein fibrils"] -->|activates| NLRP3_Inflammasome["NLRP3 Inflammasome"]
TFEB_overexpression["TFEB overexpression"] -.->|inhibits| tau_A__pathology["tau/Aβ pathology"]
TARDBP_MUTATIONS["TARDBP MUTATIONS"] -->|causes| ALS_FTD["ALS/FTD"]
TDP_43_INCLUSIONS["TDP-43 INCLUSIONS"] -->|associated with| ALS_FTD_1["ALS/FTD"]
NfL_reduction["NfL reduction"] -->|biomarker for| als["als"]
TARDBP["TARDBP"] -->|cross disease mech| ALS["ALS"]
TARDBP_2["TARDBP"] -->|cross disease mech| FTD["FTD"]
TARDBP_3["TARDBP"] -->|cross disease mech| AD_LATE["AD/LATE"]
h_cross_synth_tdp43_rna_p["h-cross-synth-tdp43-rna-proteostasis"] -->|proposes shared me| TARDBP_4["TARDBP"]
SNCA["SNCA"] -->|cross disease mech| PD_5["PD"]
style GBA1_mutations fill:#ce93d8,stroke:#333,color:#000
style PD fill:#ef5350,stroke:#333,color:#000
style TREM2_R47H_variant fill:#ce93d8,stroke:#333,color:#000
style Ad fill:#ef5350,stroke:#333,color:#000
style alpha_synuclein_fibrils fill:#4fc3f7,stroke:#333,color:#000
style NLRP3_Inflammasome fill:#ce93d8,stroke:#333,color:#000
style TFEB_overexpression fill:#4fc3f7,stroke:#333,color:#000
style tau_A__pathology fill:#4fc3f7,stroke:#333,color:#000
style TARDBP_MUTATIONS fill:#ce93d8,stroke:#333,color:#000
style ALS_FTD fill:#ef5350,stroke:#333,color:#000
style TDP_43_INCLUSIONS fill:#4fc3f7,stroke:#333,color:#000
style ALS_FTD_1 fill:#ef5350,stroke:#333,color:#000
style NfL_reduction fill:#ce93d8,stroke:#333,color:#000
style als fill:#ef5350,stroke:#333,color:#000
style TARDBP fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000
style TARDBP_2 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style TARDBP_3 fill:#4fc3f7,stroke:#333,color:#000
style AD_LATE fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_tdp43_rna_p fill:#4fc3f7,stroke:#333,color:#000
style TARDBP_4 fill:#4fc3f7,stroke:#333,color:#000
style SNCA fill:#4fc3f7,stroke:#333,color:#000
style PD_5 fill:#ef5350,stroke:#333,color:#000No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TFEB 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 TFEB, GBA1, VPS35, TMEM175.
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 |
|---|---|---|---|---|
| IF TFEB nuclear translocation is induced via mTOR inhibition (rapamycin 2mg/kg i.p. 3x/week) in aged 3xTg-AD mice crossed with TMEM175 knockout mice for 12 weeks, THEN autophagic flux will increase (L | ≥40% reduction in insoluble phospho-tau (AT8) and normalized LC3-II/LC3-I ratio in cortical tissue within 12 weeks | — no observation — | pending | 0.61 |
| IF GBA1 activity is pharmacologically enhanced (e.g., with ambroxol 600-1200 mg/day) in GBA1-associated Parkinson's disease patients for 6 months, THEN CSF glucocerebrosidase activity will increase by | ≥30% increase in CSF GCase activity and ≥25% reduction in plasma α-synuclein (Simoa) within 6 months of treatment | — no observation — | pending | 0.72 |