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.
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










Median TPM across 13 brain regions for TARDBP from GTEx v10.
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.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| 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 — | pending | 0.40 |
| 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 | be 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 — | pending | 0.40 |
| If hypothesis is true, intervention be designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activities | be designed with specific secondary structures that stabilize TDP-43 in conformations incompatible with cross-seeding activities | — no observation — | pending | 0.40 |
| If hypothesis is true, intervention competitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targets | competitively bind to TDP-43's RRM domains with greater specificity and affinity than endogenous RNA targets | — no observation — | pending | 0.40 |