Retained introns contain upstream ORFs or alternative start sites producing N-terminal peptides that contain signal sequences directing co-translational ER targeting. These aberrant peptides outcompete wild-type GBA nascent chains for SRP binding, preventing proper ER targeting of wild-type GBA. Without SRP-mediated targeting, wild-type GBA misfolds in the cytosol and is degraded by proteasome. Lysosomal delivery of residual GBA is impaired due to disrupted mannose-6-phosphate tagging. Importantly, LIMP-2 enhancement represents a therapeutic strategy independent of upstream mechanism validation.
Curated pathway from expert analysis
flowchart TD
A["SRP54/SRP68/SRP72<br/>Signal Recognition Particle"]
B["Co-Translational<br/>ER Targeting Defect"]
C["SCARB2 (LIMP2)<br/>Lysosomal Targeting"]
D["Lysosomal<br/>Proteostasis Failure"]
E["Proteostatic<br/>Stress"]
F["ER<br/>Associated Degradation"]
G["Neurodegeneration<br/>Protein Misfolding"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for SRP54 yet. Search RCSB →
Median TPM across 13 brain regions for SRP54, SRP68, SRP72 (SRP components); SCARB2 (LIMP-2) 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 SRP54, SRP68, SRP72 (SRP components); SCARB2 (LIMP-2).
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 we achieve >2-fold overexpression of LIMP-2 (SCARB2) via lentiviral transduction in iPSC-derived neurons from GBA-associated Parkinson's disease patients, THEN lysosomal GBA activity (4-MUG hydroly | Increased lysosomal GBA enzymatic activity (fluorometric assay) and increased lysosomal GBA protein (by immunoprecipitation-Western blot with mannose-6-phosphat | — no observation — | pending | 0.60 |
| IF we overexpress an N-terminal signal peptide-encoding ORF from a GBA retained intron in HEK293T cells, THEN wild-type GBA protein levels in ER-enriched fractions will decrease by >40% and cytosolic | Decreased ER-localized wild-type GBA (Western blot signal reduction) and increased proteasome-degraded GBA (K48-linked ubiquitin co-immunoprecipitation) | — no observation — | pending | 0.65 |