ID: hyp-SDA-2026-04-08-gap-pubmed-20260406-0
Hypothesis
Membrane Lipid Composition Therapeutic Modulation
Creating hostile membrane environments that prevent seed uptake or force conformational changes reducing propagation.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Creating hostile membrane environments that prevent seed uptake or force conformational changes reducing propagation
🧬 Mechanism
🔗 Mechanism from KG for HMGCR
Auto-built from this analysis's top knowledge-graph edges.
graph TD
ATP6V1A["ATP6V1A"] -->|encodes subunit of| v_ATPase["v-ATPase"]
ATP6V1A_1["ATP6V1A"] -->|encodes subunit of| lysosomal_acidification["lysosomal acidification"]
lysosomal_acidification_2["lysosomal acidification"] -->|associated with| PROTEIN_DEGRADATION["PROTEIN_DEGRADATION"]
HSPA1A["HSPA1A"] -->|regulates| PROTEIN_FOLDING["PROTEIN_FOLDING"]
PROTEIN_FOLDING_3["PROTEIN_FOLDING"] -.->|inhibits| PROTEIN_AGGREGATION["PROTEIN_AGGREGATION"]
v_ATPase_4["v-ATPase"] -->|modulates| lysosomal_pH["lysosomal pH"]
lysosomal_acidification_5["lysosomal acidification"] -->|enables| protein_degradation["protein degradation"]
protein_degradation_6["protein degradation"] -->|protects against| neurodegeneration["neurodegeneration"]
ATF5["ATF5"] -->|transcriptional ac| UPRmt["UPRmt"]
UPRmt_7["UPRmt"] -->|regulates| mitochondrial_proteostasi["mitochondrial proteostasis"]
mitochondrial_proteostasi_8["mitochondrial proteostasis"] -->|resists| seed_induced_protein_misf["seed-induced protein misfolding"]
HSPA1A_9["HSPA1A"] -->|facilitates| protein_folding["protein folding"]
style ATP6V1A fill:#ce93d8,stroke:#333,color:#000
style v_ATPase fill:#4fc3f7,stroke:#333,color:#000
style ATP6V1A_1 fill:#ce93d8,stroke:#333,color:#000
style lysosomal_acidification fill:#81c784,stroke:#333,color:#000
style lysosomal_acidification_2 fill:#81c784,stroke:#333,color:#000
style PROTEIN_DEGRADATION fill:#81c784,stroke:#333,color:#000
style HSPA1A fill:#ce93d8,stroke:#333,color:#000
style PROTEIN_FOLDING fill:#4fc3f7,stroke:#333,color:#000
style PROTEIN_FOLDING_3 fill:#4fc3f7,stroke:#333,color:#000
style PROTEIN_AGGREGATION fill:#4fc3f7,stroke:#333,color:#000
style v_ATPase_4 fill:#4fc3f7,stroke:#333,color:#000
style lysosomal_pH fill:#4fc3f7,stroke:#333,color:#000
style lysosomal_acidification_5 fill:#81c784,stroke:#333,color:#000
style protein_degradation fill:#4fc3f7,stroke:#333,color:#000
style protein_degradation_6 fill:#4fc3f7,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style ATF5 fill:#ce93d8,stroke:#333,color:#000
style UPRmt fill:#81c784,stroke:#333,color:#000
style UPRmt_7 fill:#81c784,stroke:#333,color:#000
style mitochondrial_proteostasi fill:#4fc3f7,stroke:#333,color:#000
style mitochondrial_proteostasi_8 fill:#4fc3f7,stroke:#333,color:#000
style seed_induced_protein_misf fill:#4fc3f7,stroke:#333,color:#000
style HSPA1A_9 fill:#ce93d8,stroke:#333,color:#000
style protein_folding fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis.
Supports
Anti-HMGCR immune-mediated necrotising myopathy: Addressing the remaining issues.
Supports
The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — HMGCR
No curated PDB or AlphaFold mapping for HMGCR yet. Search RCSB →
💉 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 HMGCR.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▲ 0.0%
Volatility
High
0.0535
Events (7d)
0
Price History
▲6.0%💾 Resource Usage
LLM Tokens
15,500
$0.0930
Total Cost
$0.0930
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF HMGCR is pharmacologically inhibited with simvastatin (1 μM) in human iPSC-derived dopaminergic neurons for 72 hours prior to exposure with α-synuclein preformed fibrils (PFFs), THEN intracellular | ≥40% reduction in Thioflavin T-positive cells or α-synuclein pSer129 immunoreactive puncta per neuron at 7 days post-PFF exposure | — no observation — | pending | 0.65 |
| IF membrane lipid composition is experimentally shifted toward increased polyunsaturated fatty acid (PUFA) content via DHA supplementation (10 μM, 5 days) combined with HMGCR inhibition in APP/PS1 tra | ≥50% reduction in amyloid seeding activity measured by RT-QuIC or QuIC in the contralateral hippocampus at 90 days post-dietary intervention; secondary outcome | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF HMGCR is pharmacologically inhibited with simvastatin (1 μM) in human iPSC-derived dopaminergic neurons for 72 hours prior to exposure with α-synuclein preformed fibrils (PFFs), THEN intracellular α-synuclein aggregate formation will be reduced by ≥40% compared to vehicle-treated controls, becaus
Predicted outcome: ≥40% reduction in Thioflavin T-positive cells or α-synuclein pSer129 immunoreactive puncta per neuron at 7 days post-PFF exposure
Falsification: No significant reduction in aggregate load (≤15% change from baseline) despite confirmed ≥50% HMGCR activity inhibition and ≥30% membrane cholesterol depletion as measured by cholesterol oxidase assay
pendingconf 55%
IF membrane lipid composition is experimentally shifted toward increased polyunsaturated fatty acid (PUFA) content via DHA supplementation (10 μM, 5 days) combined with HMGCR inhibition in APP/PS1 transgenic mice, THEN amyloid seed propagation and spreading to contralateral hippocampus will be reduc
Predicted outcome: ≥50% reduction in amyloid seeding activity measured by RT-QuIC or QuIC in the contralateral hippocampus at 90 days post-dietary intervention; secondar
Falsification: No significant difference in contralateral seeding activity or Aβ42 levels between intervention and control groups; equivalent spread in both hemispheres despite confirmed membrane lipid changes (elev
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
Public annotations (0)Annotate on Hypothes.is →
No public annotations yet.