Intron-retained GBA transcripts escaping nuclear retention enter the cytoplasm where the intronic sequence causes ribosome stalling. Colliding ribosomes recruit ZNF598 and GIGYF2, triggering ubiquitination of ribosomal proteins and activation of ribosome-associated quality control (RQC). This global translational repression disproportionately affects the already-low-abundance GBA transcripts, leading to cumulative protein reduction. While direct ZNF598 or GIGYF2 inhibitors carry safety risks, targeting the substrate (IR-GBA transcript) via ASO or siRNA represents a viable therapeutic strategy.
Curated pathway from expert analysis
flowchart TD
A["GBA mRNA<br/>Quality Control Defect"]
B["Ribosome<br/>Stalling"]
C["ZNF598<br/>Collision Sensor"]
D["GIGYF2<br/>Collision Response"]
E["RQC Components<br/>Targeted Decay"]
F["Nascent Chain<br/>Quality Crisis"]
G["Proteostasis<br/>Failure"]
H["Neurodegeneration<br/>PD / GBA"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for GBA mRNA; ZNF598, GIGYF2, RQC components 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 GBA mRNA; ZNF598, GIGYF2, RQC components.
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 intron-retained GBA (IR-GBA) transcripts are selectively degraded via ASO treatment in iPSC-derived neurons from homozygous GBA N370S carriers, THEN GBA protein levels will increase by ≥50% relativ | IR-GBA mRNA knockdown ≥60% will correlate with ≥50% increase in GBA protein abundance measured by ELISA or Western blot, while total cellular translation (asses | — no observation — | pending | 0.65 |
| IF ZNF598 is genetically ablated via CRISPR-Cas9 in HEK293T cells expressing an IR-GBA reporter construct, THEN global translational output will be restored to levels indistinguishable from cells lack | ZNF598 knockout will reduce ribosomal protein ubiquitination (assessed by ubiquitin immunoprecipitation at ribosome fractions) at IR-GBA transcripts and normali | — no observation — | pending | 0.58 |