Upon autophagy induction, neurons uniquely accumulate p62/SQSTM1 due to inefficient recognition of polyubiquitinated aggregates, creating an mTORC1-activating domain (MAZ)-mediated feedback loop that terminates the autophagic response prematurely. This hypothesis was substantially weakened by SKEPTIC critique due to mechanistic non-uniqueness and lack of demonstrated neuronal specificity in the p62 accumulation response compared to other cell types.
Curated pathway from expert analysis
graph TD
A["Autophagy induction in neurons"] --> B["p62/SQSTM1 accumulation due to inefficient polyubiquitin tagging"]
B --> C["MAZ domain-mediated premature mTORC1 reactivation"]
C --> D["Early autophagic response termination"]
D --> E["Incomplete aggregate and damaged organelle clearance"]
E --> F["Neuronal proteostatic stress and dysfunction"]No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for SQSTM1 yet. Search RCSB →
Median TPM across 13 brain regions for SQSTM1 (p62), mTORC1, TRAF6 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 SQSTM1 (p62), mTORC1, TRAF6.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF VPS34 activator (SAX1 analog, 10μM) is administered to p62-accumulating neurons to bypass the MAZ-mediated mTORC1 feedback loop, THEN autophagic flux (measured by LC3-II turnover + mCherry-GFP-LC3 | >50% increase in autophagic flux and >30% reduction in ubiquitin-positive aggregates after 24h VPS34 activation | — no observation — | pending | 0.30 |
| IF primary cortical neurons and age-matched astrocytes are treated with identical autophagy inducers (rapamycin 100nM for 6h), THEN neurons will exhibit significantly greater p62/SQSTM1 accumulation ( | p62 protein levels will increase >2-fold in neurons but <1.2-fold in astrocytes at 6h post-induction | — no observation — | pending | 0.35 |