ID: h-SDA-2026-04-26-gap-pubmed-20260412-094
Hypothesis
Dicer-Processed siRNA-Mediated Transcript Silencing
Retained intronic sequences contain inverted repeat elements forming long dsRNA structures recognized by Dicer, which cleaves them into siRNAs of 21-23 nucleotides.
neurodegeneration
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 4 oppose
✓ All Quality Gates Passed
🧪 Overview
Retained intronic sequences contain inverted repeat elements forming long dsRNA structures recognized by Dicer, which cleaves them into siRNAs of 21-23 nucleotides. These siRNAs loaded into AGO2 cleave complementary sequences in wild-type GBA mRNA, providing an amplification loop where one intron-retained transcript generates multiple siRNAs capable of destroying numerous normal GBA transcripts.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["GBA Loss-of-Function<br/>N370S/L444P Variants"]
B["Lysosomal GCase<br/>Activity Reduced"]
C["Glucosylceramide<br/>Substrate Accumulation"]
D["Lysosomal Dysfunction<br/>pH Dysregulation"]
E["Autophagy Impairment<br/>CMA Disruption"]
F["SNCA Accumulation<br/>Lysosomal Entrapment"]
G["Lewy Pathology<br/>PD/DLB Risk 5-fold"]
H["GBA2 Compensation<br/>Non-lysosomal GCase"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
H -.->|"partial rescue"| C
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix3 supports4 contradicts
Contradicts
No evidence that GBA introns contain inverted repeat elements required for dsRNA formation
Contradicts
Dicer-dependent siRNA pathways are primarily antiviral in mammals; endogenous siRNAs from cellular transcripts exceptionally rare
Contradicts
AGO2 slice activity requires near-perfect complementarity, not demonstrated for any GBA-derived siRNA
Contradicts
Mechanism requires specific structural elements not demonstrated in GBA introns
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — DICER1
No curated PDB or AlphaFold mapping for DICER1 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for DICER1 (Dicer); AGO2 (EIF2C2); TNRC6A (GW182) 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 DICER1 (Dicer); AGO2 (EIF2C2); TNRC6A (GW182).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
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Stable
7d Momentum
▲ 0.0%
Volatility
High
0.2007
Events (7d)
1
Price History
▲6.9%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF Dicer catalytic activity is pharmacologically inhibited (e.g., with cevirstatin) or DICER1 is knocked down by 80%+ in cells expressing intron-retained GBA transcripts with inverted repeats, THEN th | siRNA-seq reads matching the inverted repeat regions of retained GBA introns will be reduced by >50% in Dicer-inhibited cells compared to vehicle-treated contro | — no observation — | pending | 0.65 |
| IF AGO2 is genetically knocked out (CRISPR-Cas9, frameshift mutations) or its slicer activity is inactivated (D597A mutation) in fibroblasts harboring intron-retained GBA alleles, THEN wild-type GBA m | Quantitative RT-PCR will show >2-fold increase in full-length GBA mRNA (spanning exons 1-12) in AGO2-null cells, and fluorometric GBA enzyme assay (4-MUG substr | — no observation — | pending | 0.58 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF Dicer catalytic activity is pharmacologically inhibited (e.g., with cevirstatin) or DICER1 is knocked down by 80%+ in cells expressing intron-retained GBA transcripts with inverted repeats, THEN the abundance of 21-23 nt siRNAs mapping to the sense strand of the retained intronic inverted repeat
Predicted outcome: siRNA-seq reads matching the inverted repeat regions of retained GBA introns will be reduced by >50% in Dicer-inhibited cells compared to vehicle-trea
Falsification: siRNA abundance from intronic inverted repeat sequences is unchanged or increased despite >80% DICER1 knockdown or complete Dicer catalytic inhibition, indicating Dicer-independent generation of these
pendingconf 58%
IF AGO2 is genetically knocked out (CRISPR-Cas9, frameshift mutations) or its slicer activity is inactivated (D597A mutation) in fibroblasts harboring intron-retained GBA alleles, THEN wild-type GBA mRNA levels will increase by >2-fold and GBA enzyme activity will increase by >40% within 96 hours co
Predicted outcome: Quantitative RT-PCR will show >2-fold increase in full-length GBA mRNA (spanning exons 1-12) in AGO2-null cells, and fluorometric GBA enzyme assay (4-
Falsification: GBA mRNA levels and enzyme activity remain unchanged (<20% difference) in AGO2 knockout cells compared to AGO2-wildtype controls, indicating AGO2 is not required for silencing of wild-type GBA by intr
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _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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