GBA1 deficiency leads to glucosylceramide accumulation in the inner mitochondrial membrane (as shown by lipidomics of patient fibroblasts), which directly stabilizes Miro1 protein levels by inhibiting the mitochondrial protease LONP1. Miro1 is a calcium-sensitive adaptor that tethers mitochondria to the microtubule motor complex; under normal conditions, Miro1 is ubiquitinated by the Pink1-Parkin pathway and degraded to enable mitophagosome formation. When GlcCer stabilizes Miro1, damaged mitochondria remain physically anchored, preventing their delivery to lysosomes via mitophagy. The accumulated dysfunctional mitochondria generate increased ROS, which oxidizes and inactivates GCase in a feedforward loop. Simultaneously, the impaired mitophagy prevents turnover of mitochondrial SNCA nucleation sites, as mitochondria serve as platforms for initial SNCA oligomerization in neurons. VPS35 dysfunction (as in D620N mutation) worsens this by impairing trafficking of both GCase and the mitochondria-lysosome tethering machinery. The prediction is that Miro1 knockdown or pharmacological destabilization (with relevant compounds) will restore mitophagy and break the cycle.
...Curated pathway from expert analysis
flowchart TD
A["GBA1 GCase Deficiency<br/>GlcCer Accumulation"]
B["Mitochondrial Lysosomal Contact Disruption<br/>Organelle Crosstalk Loss"]
C["LONP1 Protease Inhibition<br/>Miro1 Stabilization"]
D["Miro1 Motor Adaptor Persistence<br/>Damaged Mitochondria Stay Motile"]
E["PINK1 Parkin Mitophagy Blockade<br/>Ubiquitin Clearance Failure"]
F["Damaged Mitochondria Retention<br/>ROS and Bioenergetic Stress"]
G["SNCA Aggregation Susceptibility<br/>PD Neurodegeneration"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for 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 GBA1.
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 Miro1 is genetically knocked down (via shRNA or CRISPRi) in GBA1-deficient patient-derived neurons THEN mitochondrial-lysosomal contact site frequency (measured by MCS-anchors live-cell imaging) wi | Miro1 knockdown reduces mitochondrial-lysosomal contact site frequency and restores mitophagy flux in GBA1-deficient neurons to near-wildtype levels | — no observation — | pending | 0.65 |
| IF glucosylceramide (GlcCer) accumulation is reduced via GCase enzyme replacement (ambroxol) or substrate reduction therapy in GBA1-deficient fibroblasts THEN Miro1 protein levels will decrease by >40 | GlcCer reduction normalizes Miro1 protein levels and restores LONP1 protease activity in GBA1-deficient cells | — no observation — | pending | 0.58 |