High risk. The Expert identifies a fatal flaw: CD38 is predominantly expressed in peripheral immune cells (B cells, T cells, NK cells), not microglia. The cited 3-4 fold increase in PD substantia nigra microglia may reflect perivascular macrophage infiltration rather than intrinsic microglial CD38. Multiple clinical-stage CD38 inhibitors exist (evobrutinib approved for MS), but none are being developed for neurodegeneration. This hypothesis should not proceed without microglial-specific CD38 validation in human PD substantia nigra using single-cell approaches.
Curated pathway from expert analysis
flowchart TD
A["Target Gene: CD38"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal or Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for CD38 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 CD38.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we perform single-cell RNA sequencing (scRNA-seq) of CD45+ immune cells isolated from post-mortem Parkinson's disease substantia nigra tissue AND stratify cells by canonical microglial markers (P2R | CD38 expression (log2 normalized counts) will be significantly elevated (p<0.001) in P2RY12-negative perivascular macrophages relative to P2RY12-positive microg | — no observation — | pending | 0.65 |
| IF we administer a CNS-penetrant CD38 inhibitor (evobrutinib at 20mg/kg twice daily, blood-brain barrier penetrating formulation) to C57BL/6 mice for 4 weeks following MPTP-induced dopaminergic lesion | CD38 inhibitor treatment will show ≤10% change in p21+/Iba1+ microglial density (expected ~15 cells/field in vehicle) and ≤5% change in TH+ neuron count (expect | — no observation — | pending | 0.45 |