We propose that GBA deficiency-driven accumulation of glucosylceramide (GlcCer) in lysosomal membranes creates ordered lipid raft-like microdomains that serve as high-affinity nucleation sites for alpha-synuclein (αSyn) binding and fibrillization. The resultant αSyn oligomers directly interact with LIMP-2 (SCARB2), the mannose-6-phosphate receptor responsible for trafficking pro-GBA from ER to lysosome, impairing its function and causing further GBA mislocalization. This creates a self-reinforcing bidirectional loop. Testable prediction: pharmacological reduction of GlcCer via GZ/SAR402671 will reduce αSyn seeding susceptibility in patient-derived neurons, measured by ThT fluorescence and seeding assays, prior to detectable changes in total αSyn levels. Blocking this lipid-mediated nucleation interface would break the loop upstream of both aggregation and trafficking impairment.
Curated pathway from expert analysis
flowchart TD
A["GBA Loss of Function<br/>Glucosylceramide Accumulation"]
B["Lipid Raft<br/>Microdomain Formation"]
C["Alpha-Synuclein<br/>Aggregation Nucleation"]
D["LIMP-2-Mediated<br/>GBA Trafficking Deficit"]
E["Synucleinopathy<br/>Propagation"]
F["GBA as<br/>Lipid-Nucleation Target"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for GBA 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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF a synthetic competitive peptide (50 μM) corresponding to the LIMP-2 binding domain (residues 269-290) is applied to iPSC-derived neurons from GBA-PD patients, THEN lysosomal GBA activity (measured | Blocking αSyn-LIMP-2 interaction with a competitive peptide restores LIMP-2 trafficking function and GBA localization to lysosomes | — no observation — | pending | 0.65 |
| IF human iPSC-derived dopaminergic neurons from GBA-PD patients (homozygous N370S or heterozygous L444P) are treated with a brain-penetrant GlcCer synthase inhibitor (GZ/SAR402671, 1 μM) for 7 days, T | GlcCer reduction (≥50% by LC-MS/MS) precedes and is quantitatively correlated with reduced αSyn seeding susceptibility, with no concurrent change in total αSyn | — no observation — | pending | 0.72 |