Transglutaminase-2 creates covalent cross-links between lysine and glutamine residues shared across tau, α-synuclein, and TDP-43, stabilizing heterologous aggregates. Selective TG2 inhibitors targeting the cross-seeding-specific substrate sites could disrupt mixed aggregate formation while preserving physiological TG2 functions.
Curated pathway from expert analysis
graph TD
A["""Neuroinflammation<br/>& Calcium Dysregulation"""] -->|"Ca2+ Influx"| B["TG2 Activation<br/>(Transglutaminase-2)"]
B -->|"Isopeptide Bond<br/>Formation"| C["Tau Cross-Linking<br/>& Aggregation"]
B -->|"Protein Cross-Linking"| D["Abeta Oligomer<br/>Stabilization"]
B -->|"ECM Cross-Linking"| E["BBB Disruption<br/>& Matrix Stiffening"]
B -->|"NF-kappaB Activation"| F["Pro-inflammatory<br/>Cytokine Cascade"]
C --> G["Neurofibrillary<br/>Tangle Formation"]
D --> H["Amyloid Plaque<br/>Stabilization"]
E --> I["Peripheral Immune<br/>Cell Infiltration"]
F --> J["Chronic<br/>Neuroinflammation"]
G --> K["Neuronal Death<br/>& Cognitive Decline"]
H --> K
I --> J
J --> K
L["""TG2 Inhibitor<br/>Therapy"""] -->|"Selective Active-Site<br/>Blockade"| M["TG2 Cross-Linking<br/>Inhibition"]
M -->|"Reduced Tau<br/>Cross-Linking"| N["Prevented Tangle<br/>Formation"]
M -->|"Reduced Abeta<br/>Stabilization"| O["Enhanced Abeta<br/>Clearance"]
M -->|"Preserved BBB<br/>Integrity"| P["Reduced Immune<br/>Infiltration"]
M -->|"Suppressed NF-kappaB"| Q["Reduced<br/>Neuroinflammation"]
N --> R["Neuroprotection &<br/>Cognitive Preservation"]
O --> R
P --> R
Q --> R
style A fill:#ff8a80,stroke:#d32f2f,color:#000
style L fill:#4fc3f7,stroke:#2196f3,color:#000
style R fill:#81c784,stroke:#4caf50,color:#000
style K fill:#ffab91,stroke:#e64a19,color:#000







No curated PDB or AlphaFold mapping for TGM2 yet. Search RCSB →
Median TPM across 13 brain regions for TGM2 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 TGM2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention provide non-invasive measures of enzyme activity and inhibitor penetration | provide non-invasive measures of enzyme activity and inhibitor penetration | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention be most beneficial, positioning this strategy for prodromal or mild cognitive impairment stages rather than established dementia | be most beneficial, positioning this strategy for prodromal or mild cognitive impairment stages rather than established dementia | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention enable non-invasive monitoring of enzyme activity in living brains | enable non-invasive monitoring of enzyme activity in living brains | — no observation — | pending | 0.60 |