Selective c-Abl Inhibition Promotes α-Synuclein Clearance via Autophagy
🧪 Overview
c-Abl kinase is activated in PD substantia nigra and phosphorylates parkin at Tyr143, inhibiting its E3 ligase activity and impairing ubiquitination of α-synuclein substrates. Selective c-Abl inhibitors (K0706) block parkin inactivation, enhancing degradation of pathological substrates. Phase 2 nilotinib trial showed safety but modest efficacy, suggesting that next-generation selective inhibitors may be needed for meaningful benefit.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["c-Abl / ABL1<br/>Kinase Activation"]
B["Mitochondrial<br/>Apoptosis"]
C["Alpha-Synuclein<br/>Phosphorylation"]
D["Parkinson<br/>Pathology"]
E["Therapeutic<br/>Inhibition"]
F["Synuclein Clearance<br/>Restoration"]
G["Neuroprotection<br/>Disease Modification"]
A --> B
A --> C
B --> D
C --> D
E --> A
E --> F
F --> G
D --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — ABL1
No curated PDB or AlphaFold mapping for ABL1 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for ABL1/c-Abl from GTEx v10.
💉 Clinical Trials
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 ABL1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF patients with idiopathic Parkinson's disease receive orally administered selective c-Abl inhibitor (K0706 at doses achieving >80% target engagement, e.g., 300mg daily) for 6 months, THEN cerebrospi | ≥25% reduction in CSF α-synuclein concentration; ≥5-point improvement in MDS-UPDRS Part III score | — no observation — | pending | 0.55 |
| IF A53T SNCA transgenic mice (Line 61) receive chronic oral K0706 (30mg/kg/day) for 8 weeks beginning at 12 months of age, THEN markers of autophagic flux (LC3-II/LC3-I ratio, p62 degradation rate) wi | ≥50% increase in LC3-II/LC3-I ratio; ≥40% reduction in α-synuclein pSer129 immunoreactive aggregates in nigrostriatal tissue | — no observation — | pending | 0.60 |
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |