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.
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:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for DICER1 yet. Search RCSB →
Median TPM across 13 brain regions for DICER1 (Dicer); AGO2 (EIF2C2); TNRC6A (GW182) from GTEx v10.
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.
No resource usage or linked notebooks recorded for this hypothesis yet.
| 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 |