ID: h-df4e435ebf
Hypothesis
RNA-binding proteins stabilize or gate the lncRNA-0021:mmu-miR-6361 duplex
An auxiliary protein, such as TDP-43, FUS, or an hnRNP family member, may bind lncRNA-0021 and/or mmu-miR-6361 to increase local concentration, expose the binding site, or stabilize the duplex once formed.
molecular neurobiology
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
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🧪 Overview
An auxiliary protein, such as TDP-43, FUS, or an hnRNP family member, may bind lncRNA-0021 and/or mmu-miR-6361 to increase local concentration, expose the binding site, or stabilize the duplex once formed. In this model, sequence complementarity is still required, but full selectivity emerges from an RBP-dependent ternary complex.
🧬 Mechanism
🧬 Curated Mechanism Pathway
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
⚖️ Evidence Matrix3 supports2 contradicts
Supports
FUS recognizes structured RNA features with high specificity, making it a plausible duplex-stabilizing factor.
Supports
TDP-43 and FUS are central to neuronal RNA metabolism and disease-linked RNA regulation.
Contradicts
Most ceRNA models do not require an obligate RBP bridge, so this adds complexity without pair-specific evidence.
Contradicts
Subcellular localization is problematic because many candidate RBPs are predominantly nuclear whereas ceRNA activity is usually cytoplasmic.
📖 Linked Papers
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/FUS/HNRNPA2B1 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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
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Timeline
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📊 Market Indicators
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF purified recombinant TDP-43, FUS, or HNRNPA2B1 protein is added to an in vitro duplex formation assay containing radiolabeled lncRNA-0021 and mmu-miR-6361, THEN the rate of duplex formation will in | A 2-fold or greater increase in RNA duplex formation kinetics when RBP is present | — no observation — | pending | 0.40 |
| IF TDP-43 (TARDBP) is knocked down using CRISPR-Cas9 in Neuro-2a cells, THEN the abundance of the lncRNA-0021:mmu-miR-6361 duplex will decrease by at least 50% within 72 hours post-transfection compar | A significant reduction in lncRNA-0021:mmu-miR-6361 duplex levels (≥50% decrease) following TDP-43 depletion | — no observation — | pending | 0.45 |
🔮 Falsifiable Predictions (2)
pendingconf 45%
IF TDP-43 (TARDBP) is knocked down using CRISPR-Cas9 in Neuro-2a cells, THEN the abundance of the lncRNA-0021:mmu-miR-6361 duplex will decrease by at least 50% within 72 hours post-transfection compared to non-targeting control, as measured by RNA immunoprecipitation followed by quantitative PCR.
Predicted outcome: A significant reduction in lncRNA-0021:mmu-miR-6361 duplex levels (≥50% decrease) following TDP-43 depletion
Falsification: Duplex abundance remains unchanged or increases despite >70% TDP-43 protein reduction, indicating RBP binding is not required for duplex formation
pendingconf 40%
IF purified recombinant TDP-43, FUS, or HNRNPA2B1 protein is added to an in vitro duplex formation assay containing radiolabeled lncRNA-0021 and mmu-miR-6361, THEN the rate of duplex formation will increase by at least 2-fold compared to protein-free conditions within 30 minutes at 37°C, as measured
Predicted outcome: A 2-fold or greater increase in RNA duplex formation kinetics when RBP is present
Falsification: No significant change in duplex formation rate (fold-change <1.5) with any of the three RBPs tested, indicating these proteins do not stabilize or gate the duplex
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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