The strongest synthesis is an indirect mechanism in glia: APOE4 promotes cholesterol sequestration in late endosome/lysosome compartments, lowering the ER-accessible cholesterol pool sensed by SCAP despite normal or elevated total cellular cholesterol. This weakens SCAP-INSIG retention, increases SREBP2 processing, and may explain the paradox of cholesterol accumulation alongside increased cholesterol biosynthesis.
Curated pathway from expert analysis
flowchart TD
A["NPC1 Protein<br/>Intracellular Cholesterol Transporter"]
B["NPC1 Mutation<br/>Lysosomal Cholesterol Accumulation"]
C["Late Endosome Maturation<br/>Esterified Cholesterol Trapped"]
D["ER Calcium Dysregulation<br/>Store-Operated Entry"]
E["Mitochondrial Cholesterol<br/>Mitochondrial Membrane Rigid"]
F["Apoptosis Susceptibility<br/>Increased Neuronal Death"]
G["Axonal Transport Deficit<br/>Microtubule Disruption"]
H["Neurodegeneration<br/>Neuronal Loss in NPC Disease"]
I["Cognitive Decline<br/>Neurofibrillary Tangles"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
H --> I
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style I fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NPC1 yet. Search RCSB →
Median TPM across 13 brain regions for NPC1 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 NPC1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF ER-localized cholesterol is measured directly using an ER-targeted cholesterol biosensor (ER-CholeMIM) in live APOE4 versus APOE3 astrocytes, THEN APOE4 astrocytes will exhibit ≥35% lower ER choles | ER cholesterol concentration significantly lower in APOE4 (≥35% reduction); total cellular cholesterol unchanged between genotypes | — no observation — | pending | 0.68 |
| IF cyclodextrin-mediated enhancement of cytosolic cholesterol trafficking to the ER is applied to APOE4 homozygous iPSC-derived astrocytes, THEN SREBP2 cleavage (nuclear SREBP2/total SREBP2 ratio) wil | nuclear SREBP2 protein levels decrease ≥40%; HMG-CoA reductase activity normalized to APOE3 baseline | — no observation — | pending | 0.72 |