early PD proteogenomic hubs that are both causal enough and accessible enough to perturb should produce a measurable proximal phenotype before late disease pathology. The decisive test is multi-omics network centrality, druggability scoring, interactome validation, and SNCA iPSC-neuron perturbation assays.
Curated pathway from expert analysis
flowchart TD
A["PD Proteogenomic Hub Identification<br/>Multi-Omics Network Analysis"]
B["Causal Enough: Disease-Associated<br/>Genetics and Transcriptomics Convergence"]
C["Accessible Enough to Perturb<br/>Drug-Targetable Nodes (kinases, phosphatases)"]
D["Stage-Specific Hub Activation<br/>Early vs Late PD Neurodegeneration"]
E["Perturbation-First Validation<br/>CRISPRi, small molecules, siRNA"]
F["Druggable Target Candidates<br/>Therapeutic Intervention Points"]
G["Disease-Modifying PD Therapy<br/>Hub-Targeted Neuroprotection"]
A --> B
A --> C
B --> D
C --> D
D --> E
E --> F
F --> G
style A fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
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.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we stratify early-stage PD patients (disease duration <3 years, H&Y stage ≤2) by druggable proteogenomic hub accessibility scores (CNS penetrance ≥30%, DrugBank hit) and compare to age-matched cont | High-hub-accessibility PD patients will show ≥2-fold increase in CSF synaptic dysfunction biomarkers compared to low-accessibility PD patients and ≥3-fold incre | — no observation — | pending | 0.68 |
| IF we CRISPR-perturb top-ranked proteogenomic hub genes (identified by multi-omics network centrality >2 SD above mean) in SNCA-A53T iPSC-derived dopaminergic neurons, THEN we will observe a significa | Hub-perturbed neurons will show ≥40% reduction in synaptic vesicle markers and ≥50% decrease in spontaneous firing rate relative to control perturbations. | — no observation — | pending | 0.72 |