Neurons uniquely express the PP2A Bβ1 regulatory subunit forming a phosphatase complex that selectively dephosphorylates and activates ULK1 at Ser757 but not Ser317, creating a dominant-negative ULK1 activation state refractory to most autophagy induction strategies. SKEPTIC critique weakened this by noting PPP2R2B is 'neuron-enriched' not 'neuron-exclusive', and the selective dephosphorylation specificity lacks structural validation. DOMAIN_EXPERT identifies this as high-risk requiring structural data on PP2A-Bβ1:ULK1 interface before clinical investment.
Curated pathway from expert analysis
flowchart TD
A["PPP2R2B PP2A Regulatory<br/>B55alpha Subunit"]
B["PP2A Heterotrimeric Complex<br/>Catalytic and Scaffold"]
C["Tau Dephosphorylation<br/>Ser262/396 Sites"]
D["AKT and MYC Regulation<br/>Cell Survival Signaling"]
E["PPP2R2B Methylation<br/>LEAVES.1 Long Noncoding RNA"]
F["PPP2R2B Silencing<br/>Hyperphosphorylated Tau Accumulation"]
G["PP2A Activators<br/>DT-061 or Peptide Activators"]
A --> B
B --> C
B --> D
E -.->|"reduces"| B
F -.->|"causes"| C
G -.->|"restores"| B
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 PPP2R2B yet. Search RCSB →
Median TPM across 13 brain regions for PPP2R2B, ULK1 complex 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 PPP2R2B, ULK1 complex.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF the PP2A-Bβ1 holoenzyme selectively dephosphorylates ULK1 at Ser757 while sparing Ser317 (as hypothesized), THEN in vitro phosphatase assays using purified recombinant PP2A-Bβ1 complex incubated wi | PP2A-Bβ1 will dephosphorylate ULK1 Ser757 at least twice as fast as Ser317 in vitro, confirming substrate selectivity | — no observation — | pending | 0.35 |
| IF neuronal expression of PP2A-Bβ1 creates a dominant-negative ULK1 state refractory to mTOR inhibition, THEN siRNA-mediated knockdown of PPP2R2B (≥70% knockdown efficiency) in primary mouse cortical | PPP2R2B knockdown will restore autophagy sensitivity to mTOR inhibition, with rapamycin increasing LC3-II/LC3-I ratio in neurons to levels comparable to PPP2R2B | — no observation — | pending | 0.40 |