ID: h-74cfd51e
Hypothesis
Phosphatidylserine Decarboxylase (PISD) Restoration to Correct Mitochondrial Membrane PS Asymmetry in AD Neurons
Phosphatidylserine Decarboxylase (PISD) Restoration to Correct Mitochondrial Membrane PS Asymmetry in AD Neurons.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 5 oppose
✓ All Quality Gates Passed
🧪 Overview
Phosphatidylserine Decarboxylase (PISD) Restoration to Correct Mitochondrial Membrane PS Asymmetry in AD Neurons
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["PISD Restoration<br/>Phosphatidylserine Decarboxylase"]
B["Mitochondrial Membrane<br/>PS Asymmetry Correction"]
C["Apoptosis Sensitivity<br/>Restored to Normal"]
D["Cell Death Threshold<br/>Properly Calibrated"]
E["Neuronal Survival<br/>Enhanced"]
F["PISD as<br/>Mitochondrial Integrity Target"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
⚖️ Evidence Matrix4 supports5 contradicts
Supports
PISD expression is significantly downregulated in AD prefrontal cortex, correlating inversely with Braak staging
Supports
PS externalization to outer mitochondrial membrane triggers BAX activation and cytochrome c release in AD neurons
Supports
PE deficiency impairs APP trafficking through secretory pathway and shifts processing toward amyloidogenic β-cleavage
Supports
No PISD-targeted programs in any indication—completely unencumbered intellectual property landscape
Expert assessment
Contradicts
PISD downregulation may be downstream of proteostatic stress rather than primary initiator
Skeptic critique
Contradicts
PISD has dual mitochondrial/nuclear localization—restoring one compartment may disrupt RNA splicing in the other
Contradicts
PS externalization triggering BAX was demonstrated with exogenous Aβ in cell culture—chronic exposure in human AD brain may differ
Skeptic critique
Contradicts
Brain PE content is preserved in AD, with increases in mitochondrial PE observed in some studies
Contradicts
Mitochondrial dysfunction in AD may be driven by mtDNA deletions and impaired dynamics—not directly addressable by PISD restoration
Skeptic critique
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — PISD
No curated PDB or AlphaFold mapping for PISD yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for PISD from GTEx v10.
💉 Clinical Trials
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 PISD.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF PISD restoration normalizes mitochondrial PS asymmetry in AD neurons THEN neuronal basal oxygen consumption rate (OCR) will increase by at least 20 % within 4 weeks of PISD overexpression. | A ≥20 % rise in basal mitochondrial OCR compared with vehicle‑treated AD neurons. | — no observation — | pending | 0.65 |
| IF PISD is overexpressed via AAV-mediated transduction in primary cortical neurons derived from 5xFAD AD mice THEN mitochondrial membrane phosphatidylserine asymmetry, as quantified by flow cytometric | At least a 30 % decrease in external phosphatidylserine on isolated brain mitochondria, measured by annexin V positivity. | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF PISD is overexpressed via AAV-mediated transduction in primary cortical neurons derived from 5xFAD AD mice THEN mitochondrial membrane phosphatidylserine asymmetry, as quantified by flow cytometric annexin V binding to MitoTracker‑positive mitochondria, will be reduced by at least 30 % within 14
Predicted outcome: At least a 30 % decrease in external phosphatidylserine on isolated brain mitochondria, measured by annexin V positivity.
Falsification: No statistically significant reduction (p > 0.05) or an increase in mitochondrial annexin V binding after PISD overexpression.
pendingconf 65%
IF PISD restoration normalizes mitochondrial PS asymmetry in AD neurons THEN neuronal basal oxygen consumption rate (OCR) will increase by at least 20 % within 4 weeks of PISD overexpression.
Predicted outcome: A ≥20 % rise in basal mitochondrial OCR compared with vehicle‑treated AD neurons.
Falsification: No significant change (p > 0.05) or a decrease in basal OCR following PISD restoration.
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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