Healthy astrocytes release HSP70-HSP40 chaperone complexes that enter motor neurons and prevent stress-induced RBP aggregation by stabilizing ribosomal assembly and inhibiting stress granule nucleation. VCP-mutant astrocytes show ER stress-induced secretion defects reducing HSP70 release. The hypothesis is weakened by thin evidence that extracellular HSP70 enters neurons in sufficient amounts to directly suppress intracellular aggregation.
Curated pathway from expert analysis
flowchart TD
A["VCP/p97 AAA+ ATPase<br/>CHIP-Dependent Degradation Complex"]
B["ER-Associated Degradation (ERAD)<br/>Ubiquitinated Substrate Extraction"]
C["AGFG1 and ArfGAP1 Interaction<br/>Vesicle Trafficking and Autophagosome Maturation"]
D["TDP-43 and FUS Extraction<br/>Nuclear Quality Control Failure Compensation"]
E["VCP Mutation (Multisystem Proteinopathy)<br/>Degeneration of Neurons and Muscle"]
F["Inclusion Body Myopathy and Frontotemporal Dementia<br/>Pathologic Aggregate Accumulation"]
G["VCP Inhibitor Therapeutic Strategy<br/>Preclinical Validation Needed"]
A --> B
B --> C
C --> D
E --> F
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for HSPA1A; yet. Search RCSB →
Median TPM across 13 brain regions for HSPA1A; DNAJB family 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 HSPA1A; DNAJB family.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF VCP-mutant astrocytes (derived from patients with VCP-related disease) are cultured under standard conditions for 48 hours, THEN the concentration of extracellular HSP70/HSP40 complexes in the cond | At least 30% reduction in secreted HSP70 (and co‑chaperone DNAJB1) levels in VCP‑mutant astrocyte-conditioned medium as quantified by ELISA. | — no observation — | pending | 0.55 |
| IF primary mouse motor neurons are treated with recombinant HSP70‑HSP40 complex (1 µg/mL) and exposed to oxidative stress (0.5 mM H₂O₂) for 24 hours, THEN the number of TDP‑43 or FUS aggregates per ne | ≥40% decrease in immunofluorescently counted RBP aggregate foci per neuron and ≥20% improvement in neuronal viability (MTT assay) in HSP70‑HSP40‑treated culture | — no observation — | pending | 0.45 |