🧪
hypothesis

TDP-43 LLPS and proteostasis dysregulation in ALS/FTD

Hypothesis

TDP-43 LLPS and proteostasis dysregulation in ALS/FTD

TDP-43 stress-granule entry and liquid-liquid phase separation may transition from reversible condensates into pathological aggregates when chaperone disassembly and post-translational regulation fail.
🧬 TARDBP🩺 neurodegeneration🎯 Composite 60%💱 $0.55▼7.3%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 2 oppose
✓ All Quality Gates Passed
Mechanistic 0.76 (15%) Evidence 0.70 (15%) Novelty 0.66 (12%) Feasibility 0.46 (12%) Impact 0.66 (12%) Druggability 0.42 (10%) Safety 0.48 (8%) Competition 0.60 (6%) Data Avail. 0.72 (5%) Reproducible 0.58 (5%) KG Connect 0.50 (8%) 0.600 composite
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🧪 Overview

TDP-43 stress-granule entry and liquid-liquid phase separation may transition from reversible condensates into pathological aggregates when chaperone disassembly and post-translational regulation fail. The therapeutic opportunity is biologically compelling but not yet product-shaped; success requires restoring nuclear TDP-43 function and RNA-splicing integrity, not only dissolving inclusions.

🧬 Mechanism

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix4 supports2 contradicts
Supports
TDP-43 forms stress granules through LLPS under physiological stress conditions.
PMID:24670997
Supports
Pathological TDP-43 aggregates colocalize with stress-granule markers in ALS tissue.
PMID:28661562
Supports
TARDBP mutations cause familial ALS, confirming disease relevance.
PMID:19479373
Supports
TDP-43 frameshift mutations alter LLPS behavior.
PMID:31853077
Contradicts
LLPS-to-aggregation is plausible but not therapeutically settled, and inclusions may be downstream of broader nuclear loss-of-function and proteostasis failure.
PMID:38029395
Contradicts
Stress-granule colocalization does not prove stress granules seed disease in vivo.
PMID:NA
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — TARDBP

🧬 PDB 4BS2 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

💉 Clinical Trials

No clinical trials data linked to this hypothesis yet.

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No DepMap CRISPR Chronos data found for TARDBP.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

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💾 Resource Usage

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