Dysbiotic bacteria compromise intestinal barrier integrity through zonulin pathway activation, allowing bacterial antigens and α-synuclein oligomers to enter systemic circulation and seed CNS pathology. Targeted tight junction stabilizers could prevent this peripheral-to-central disease propagation.
Curated pathway from expert analysis
graph TD
A["Dysbiotic Bacteria<br/>E. coli, gram-negative"]
B["LPS Endotoxin<br/>Release"]
C["TLR4 Activation<br/>Inflammatory Signaling"]
D["MLCK Activation<br/>Phosphorylation"]
E["Tight Junction<br/>Disruption"]
F["CLDN1, OCLN, ZO1<br/>Downregulation"]
G["Gut Barrier<br/>Permeability"]
H["alpha-Synuclein<br/>Aggregation"]
I["Vagal Nerve<br/>Transmission"]
J["CNS alpha-Synuclein<br/>Propagation"]
K["Neurodegeneration<br/>Progression"]
L["Tight Junction<br/>Stabilizers"]
M["Probiotic<br/>Intervention"]
A -->|"produces"| B
B -->|"binds"| C
C -->|"activates"| D
D -->|"phosphorylates"| E
E -->|"reduces"| F
F -->|"increases"| G
G -->|"promotes"| H
H -->|"travels via"| I
I -->|"spreads"| J
J -->|"causes"| K
L -->|"stabilizes"| F
M -->|"restores"| A
style A fill:#ef5350,color:#0d0d1a
style B fill:#ef5350,color:#0d0d1a
style C fill:#ef5350,color:#0d0d1a
style D fill:#ef5350,color:#0d0d1a
style E fill:#ef5350,color:#0d0d1a
style F fill:#ce93d8,color:#0d0d1a
style G fill:#ef5350,color:#0d0d1a
style H fill:#ef5350,color:#0d0d1a
style I fill:#4fc3f7,color:#0d0d1a
style J fill:#ef5350,color:#0d0d1a
style K fill:#ffd54f,color:#0d0d1a
style L fill:#81c784,color:#0d0d1a
style M fill:#81c784,color:#0d0d1aNo curated PDB or AlphaFold mapping for CLDN1 yet. Search RCSB →
Median TPM across 13 brain regions for CLDN1, OCLN, ZO1, MLCK from GTEx v10.
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 CLDN1, OCLN, ZO1, MLCK.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention address the upstream inflammatory triggers while tight junction stabilizers provide direct structural support, potentially achieving superior barrier restoration co | address the upstream inflammatory triggers while tight junction stabilizers provide direct structural support, potentially achieving superior barrier restoratio | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention sequester pathological species in the gut, preventing their systemic dissemination even in the presence of barrier dysfunction | sequester pathological species in the gut, preventing their systemic dissemination even in the presence of barrier dysfunction | — no observation — | pending | 0.60 |