ID: hypothesis-h-7693c291
Hypothesis

RNA-Binding Competition Therapy for TDP-43 Cross-Seeding

Synthetic RNA aptamers designed to competitively bind TDP-43's RNA recognition motifs could prevent its interaction with tau and α-synuclein mRNAs, thereby blocking the RNA-mediated cross-seeding mechanism.
🧬 TARDBP🩺 neurodegeneration🎯 Composite 46%💱 $0.45▼28.6%archived
EvidencePending (0%)📖 20 cit🗣 3 debates 3 support 3 oppose
✓ All Quality Gates Passed
Mechanistic 0.50 (15%) Evidence 0.40 (15%) Novelty 0.85 (12%) Feasibility 0.25 (12%) Impact 0.45 (12%) Druggability 0.30 (10%) Safety 0.25 (8%) Competition 0.75 (6%) Data Avail. 0.35 (5%) Reproducible 0.30 (5%) KG Connect 0.79 (8%) 0.465 composite
🏆 ChallengeSolve: RNA binding protein dysregulation across ALS FTD and AD$119K →

🧪 Overview

Synthetic RNA aptamers designed to competitively bind TDP-43's RNA recognition motifs could prevent its interaction with tau and α-synuclein mRNAs, thereby blocking the RNA-mediated cross-seeding mechanism. This approach targets the unique ability of TDP-43 to recruit other proteins through RNA scaffolding.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["TDP-43 / TARDBP"] --> B["RNA Processing Functions"]
    B --> C["Splicing Regulation"]
    B --> D["RNA Transport"]
    B --> E["RNA Stability"]

    F["Pathological Conditions"] --> G["Cytoplasmic Mislocalization"]
    G --> H["Hyperphosphorylation"]
    H --> I["TDP-43 Aggregation"]
    I --> J["Cross-Seeding with Other Proteins"]
    J --> K["ALS/FTD Pathology"]

    L["RNA-Binding Competition Therapy"] --> M["Designed RNA Decoys"]
    M --> N["Compete for TDP-43 RNA-Binding Domain"]
    N --> O["Sequester TDP-43 in Soluble Form"]

    O --> P["Prevent Cytoplasmic Aggregation"]
    O --> Q["Block Cross-Seeding"]
    O --> R["Preserve Some RNA Processing"]

    P --> S["Reduced TDP-43 Inclusions"]
    Q --> T["Prevented Prion-like Spread"]
    R --> U["Maintained Cellular Function"]

    S --> V["Neuroprotection in ALS/FTD"]
    T --> V
    U --> V

    style A fill:#264653,stroke:#ffd54f,color:#e0e0e0
    style F fill:#4a1942,stroke:#ce93d8,color:#e0e0e0
    style L fill:#1a3a4a,stroke:#4fc3f7,color:#e0e0e0
    style V fill:#2a3a1a,stroke:#c5e1a5,color:#e0e0e0

⚖️ Evidence

⚖️ Evidence Matrix3 supports3 contradicts
Supports
TDP-43 binds tau mRNA and regulates its translation
Supports
RNA molecules can template protein aggregation and cross-seeding
Supports
Synthetic aptamers successfully modulate TDP-43 RNA interactions
Contradicts
TDP-43 RNA binding is essential for normal cellular function, making competitive inhibition potentially toxic
Contradicts
RNA aptamers show poor CNS penetration and rapid degradation
Contradicts
TDP-43 pathology often involves loss rather than gain of RNA binding function
📖 Linked Papers (23)Export BibTeX ↗
Figure 1
Figure 1
Imaging and Pathological Data for the TDP-C Cases With Rare Genetic Variants of Interest (A) Neuroimaging for the probable TDP-C case of svPPA with FIG4 varia...
Figures
Figures
Figures available at source paper (no open-access XML found).
Fig. 1
Fig. 1
Representation of the components of our controller design architecture. a , Depiction of the learning loop. The controller sends voltage commands on the basis o...
Fig. 2
Fig. 2
Fundamental capability demonstration. Demonstration of plasma current, vertical stability, position and shape control. Top, target shape points with 2 cm radius...
Extended Data Fig. 1
Extended Data Fig. 1
Characterizations of GFP-hTDP-43 expression in a neonatal TDP-43 mouse model. GFP-hTDP-43 expression was induced via intracerebroventricular injection of AAV9.C...
Extended Data Fig. 2
Extended Data Fig. 2
Characterizations of motor deficits and neuronal loss in a neonatal TDP-43 mouse model. GFP-hTDP-43 expression was induced via intracerebroventricular injection...
Fig. 1
Fig. 1
Protein structure of transactive response DNA binding protein of 43 kDa (TDP-43). TDP-43 is a 414 amino acid protein with a nuclear localization sequence (NLS) ...
Fig. 2
Fig. 2
Representative images of TDP-43 pathology subtypes in FTLD-TDP brains. (A) Immunohistochemistry with an anti-phosphorylated-TDP-43 antibody (pSer409/pSer410) sh...
Figures
Figures
Figures available at source paper (no open-access XML found).
Figures
Figures
Figures available at source paper (no open-access XML found).
Figure 1
Figure 1
No caption available
Figure S1
Figure S1
Elevated NF-κB and Type I IFN Signaling Because of TDP-43 In Vitro , Related to Figure 1 (A) Doxycycline (Dox inducible wild-type (WT) or ALS mutant (Q331K) T...
Figures
Figures
Figures available at source paper (no open-access XML found).
Figure 1
Figure 1
Comparison of TDP-43 RNA binding in healthy and FTLD-TDP brain (a) To validate specificity of TDP-43 antibody for iCLIP, the 32 P-labelled RNA bound to TDP-43...
Figure 2
Figure 2
TDP-43 binding motif analysis (a) z-scores of penamer occurrence within the 61 nt sequence surrounding all crosslink sites (−30 nt to +30 nt) are shown for hea...
Amyotrophic lateral sclerosis.
Orphanet journal of rare diseases (2009) · PubMed:19192301 ↗
1 figure
Figures
Figures
Figures available at source paper (no open-access XML found).
📙 Related Wiki Pages (15)

🏥 Translation

🧬 3D Protein Structure — TARDBP

🧬 PDB 4BS2 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for TARDBP from GTEx v10.

Cerebellar Hemisphere131 Cerebellum115median TPM (GTEx v10)

💉 Clinical Trials (3)Relevance: 24%

0
Active
0
Completed
1,610
Total Enrolled
ENROLLING_BY_INVITATION·NCT06875739 · Fondazione Don Carlo Gnocchi Onlus
310 enrolled · 2025-02-14 · → 2026-10-01
The aim of the study is to validate a salivary test that allows for rapid and accurate objective diagnosis in the context of neurodegenerative diseases, a complex of diseases that includes Alzheimer's
Neurodegenerative Disorders Parkinson Disease Alzheimer Disease
RECRUITING·NCT06339190 · Monash University
1,000 enrolled · 2021-08-01 · → 2025-12
This cohort study aims to determine if a blood test can aid with diagnosing dementia in anyone presenting with cognitive complaints to a single healthcare network. The investigators will measure level
Neurodegenerative Diseases Dementia
Venepuncture
RECRUITING·NCT03865420 · Columbia University
300 enrolled · 2018-09-11 · → 2027-01
This program provides family members of individuals with familial ALS the opportunity to contribute to research focused on learning more about why motor neuron degeneration begins and how or why it pr
ALS

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Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

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No DepMap CRISPR Chronos data found for TARDBP.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development
Cost
$0
Timeline
2.0 years

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📊 Market Indicators

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💾 Resource Usage

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36,356
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Total Cost
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🔮 Predictions

🔎 Predictions vs Observations4 predictions · 0 with recorded observations
PredictionPredictedObservedStatusConf
If hypothesis is true, intervention be engineered to contain optimized UG/GU-rich sequences or novel binding motifs identified through systematic evolution of ligands by exponential enrichment (SELEX)be engineered to contain optimized UG/GU-rich sequences or novel binding motifs identified through systematic evolution of ligands by exponential enrichment (SE— no observation —pending0.40
If hypothesis is true, intervention be designed to specifically target TDP-43's RNA recognition motifs (RRMs), thereby disrupting its aberrant interactions with tau (MAPT) and α-synuclein (SNCA) mRNAsbe designed to specifically target TDP-43's RNA recognition motifs (RRMs), thereby disrupting its aberrant interactions with tau (MAPT) and α-synuclein (SNCA) m— no observation —pending0.40
If hypothesis is true, intervention be designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activitiesbe designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activities— no observation —pending0.40
If hypothesis is true, intervention competitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targetscompetitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targets— no observation —pending0.40
🔮 Falsifiable Predictions (4)
pendingconf 40%
If hypothesis is true, intervention competitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targets
Predicted outcome: competitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targets
Falsification: Intervention fails to competitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targets
pendingconf 40%
If hypothesis is true, intervention be engineered to contain optimized UG/GU-rich sequences or novel binding motifs identified through systematic evolution of ligands by exponential enrichment (SELEX)
Predicted outcome: be engineered to contain optimized UG/GU-rich sequences or novel binding motifs identified through systematic evolution of ligands by exponential enri
Falsification: Intervention fails to be engineered to contain optimized UG/GU-rich sequences or novel binding motifs identified through systematic evolution of ligands by exponential enrichment (SELEX)
pendingconf 40%
If hypothesis is true, intervention be designed to specifically target TDP-43's RNA recognition motifs (RRMs), thereby disrupting its aberrant interactions with tau (MAPT) and α-synuclein (SNCA) mRNAs
Predicted outcome: be designed to specifically target TDP-43's RNA recognition motifs (RRMs), thereby disrupting its aberrant interactions with tau (MAPT) and α-synuclei
Falsification: Intervention fails to be designed to specifically target TDP-43's RNA recognition motifs (RRMs), thereby disrupting its aberrant interactions with tau (MAPT) and α-synuclein (SNCA) mRNAs
pendingconf 40%
If hypothesis is true, intervention be designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activities
Predicted outcome: be designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activities
Falsification: Intervention fails to be designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activities
Related Entities
Metadata
statusproposed
diseaseneurodegeneration
target_geneTARDBP
target_pathwayNone
_schema_version1
composite_score0.44000000000000006
📊 Evidence Profile Foundational
Evidence Balance
+0%
Certainty
100%
Debates
0
Incoming
1422
Outgoing
154
0 supporting 0 contradicting 0 neutral
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