TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Cascade in Motor Neurons
🧪 Overview
TDP-43 aggregates sequester hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), a critical hub coordinating early endosome-to-autophagosome cargo delivery. In motor neurons where TDP-43 nuclear loss and cytoplasmic aggregation occurs early in ALS, HGS is functionally depleted, creating specific vulnerability where upstream autophagy induction cannot compensate for downstream cargo recognition failure. This hypothesis survived critique due to its mechanistic specificity for motor neurons and direct connection to the hallmark pathology of >95% of ALS cases.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["TARDBP/TDP-43<br/>Nuclear RNA-Binding Protein"]
B["Stress or Mutation<br/>ALS/FTD Trigger"]
C["TDP-43 Mislocalization<br/>Cytoplasmic Accumulation"]
D["Nuclear TDP-43 Depletion<br/>Cryptic Exon Inclusion"]
E["TDP-43 Aggregates<br/>Ubiquitin+ Phospho+ Inclusions"]
F["Splicing Dysregulation<br/>STMN2/UNC13A Targets"]
G["Synaptic Failure<br/>Motor Neuron Degeneration"]
A --> B
B --> C
C --> D
C --> E
D --> F
E --> G
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TARDBP
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TARDBP (TDP-43), HGS, PYGB 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 TARDBP (TDP-43), HGS, PYGB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF TDP-43 nuclear export is induced by arsenic trioxide (5 μM, 48h) in human iPSC-derived motor neurons versus cortical neurons, THEN motor neurons will show ≥60% greater HGS depletion and ≥50% higher | Motor neurons exhibit significantly greater HGS loss (Western blot) and increased apoptotic markers (cleaved caspase-3) compared to cortical neurons following e | — no observation — | pending | 0.38 |
| IF TARDBP is knocked down by ≥70% in human iPSC-derived motor neurons for 7 days, THEN HGS protein levels will decrease by ≥50% and p62/SQSTM1 cargo delivery to lysosomes will be impaired by ≥40% comp | Significant reduction in HGS protein (Western blot) and decreased colocalization of p62 with LAMP2 lysosomal marker (confocal microscopy) in motor neurons with | — no observation — | pending | 0.45 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |