SNCA conformer propagation across PD, DLB, and MSA
🧪 Overview
Shared mechanism across PD, DLB, MSA: SNCA mutations and alpha-synuclein inclusions define neuronal Lewy pathology in PD/DLB, while MSA shows oligodendroglial alpha-synuclein inclusions. A shared misfolded-alpha-synuclein seeding axis likely diverges by host cell proteostasis and lipid environment, explaining overlapping proteinopathy with distinct anatomy.
Falsifiable prediction: Patient-derived alpha-synuclein seeds from PD/DLB and MSA should induce different neuronal-versus-oligodendroglial inclusion ratios, but ASO knockdown of SNCA should lower seed amplification signal by at least 50% in all three seed classes.
Proposed experiment: Expose human dopaminergic neuron/oligodendrocyte co-cultures to characterized PD, DLB, and MSA seed extracts; treat with SNCA ASO or control; quantify pS129-SNCA, RT-QuIC/seed amplification, oligodendroglial stress, and neuronal survival.
Cross-disease confidence rationale: Canonical genetics/pathology in PD plus direct MSA glial inclusion evidence.
Internal SciDEX support: SciDEX support query found 44 matching hypotheses across 5 disease labels, including 44 with debate_count > 0.
🧬 Mechanism
Auto-built from this analysis's top knowledge-graph edges.
graph TD
SNCA["SNCA"] -->|cross disease mech| PD["PD"]
SNCA_1["SNCA"] -->|cross disease mech| DLB["DLB"]
SNCA_2["SNCA"] -->|cross disease mech| MSA["MSA"]
h_cross_synth_snca_synucl["h-cross-synth-snca-synucleinopathy"] -->|proposes shared me| SNCA_3["SNCA"]
style SNCA fill:#4fc3f7,stroke:#333,color:#000
style PD fill:#ef5350,stroke:#333,color:#000
style SNCA_1 fill:#4fc3f7,stroke:#333,color:#000
style DLB fill:#ef5350,stroke:#333,color:#000
style SNCA_2 fill:#4fc3f7,stroke:#333,color:#000
style MSA fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_snca_synucl fill:#4fc3f7,stroke:#333,color:#000
style SNCA_3 fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
🏥 Translation
🧬 3D Protein Structure — SNCA
💉 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 SNCA.
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 |
|---|---|---|---|---|
| Patient-derived alpha-synuclein seeds from PD/DLB and MSA should induce different neuronal-versus-oligodendroglial inclusion ratios, but ASO knockdown of SNCA should lower seed amplification signal by | If this mechanism is real, then Patient-derived alpha-synuclein seeds from PD/DLB and MSA should induce different neuronal-versus-oligodendroglial inclusion rat | — no observation — | pending | 0.84 |
▸Metadatasource: v1_phase_c_backfill · origin_type: cross_disease_synthesis
| source | v1_phase_c_backfill |
| origin_type | cross_disease_synthesis |
| _schema_version | 1 |