The classic butyrate neuroprotection narrative likely depends on pharmacologic exposure sufficient for HDAC inhibition, not on the low systemic concentrations realistically achievable with diet or probiotics. This should be treated as a negative control or deprioritized mechanism rather than a leading therapeutic explanation for physiologic SCFA effects.
Curated pathway from expert analysis
flowchart TD
A["Transcription Factor Recruitment<br/>Histone Deacetylase Corepressor Complex"]
B["HDAC1/HDAC2 Rpd3L Engagement<br/>Nascent Transcript Association"]
C["Inflammatory Gene Repression<br/>NF-kB and STAT1 Target Suppression"]
D["Microglial Homeostasis<br/>Pro-inflammatory Resolution"]
E["HDAC1/HDAC2 Inhibitor Exposure<br/>Chromatin Opening and Reactivation"]
F["Epigenetic Plasticity Restoration<br/>Gene Program Rebalancing"]
A --> B
B --> C
C --> D
E --> F
F -.->|"counteracts"| B
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#1b5e20,stroke:#81c784,color:#81c784
style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for HDAC1 yet. Search RCSB →
Median TPM across 13 brain regions for HDAC1/HDAC2 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 HDAC1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary cortical neurons are treated with physiologically relevant SCFA concentrations (butyrate 0.1–1 mM or propionate 0.05–0.5 mM for 48 hours), THEN neuronal HDAC activity will not decrease by m | HDAC activity assays (fluorometric) will show ≤15% inhibition at all physiological SCFA concentrations tested, while pharmacologic controls (5 mM butyrate) will | — no observation — | pending | 0.78 |
| IF mice with AAV-mediated alpha-synuclein overexpression are administered oral SCFA (butyrate 150 mg/kg/day or propionate 100 mg/kg/day) for 12 weeks to achieve physiological plasma concentrations (≤1 | Stereological quantification of pSer129-positive inclusions in striatum will show no significant difference (≤20% change) between physiologic SCFA treatment and | — no observation — | pending | 0.72 |