Mechanistic description
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.
Evidence for (3)
PPP2R2B is neuron-enriched and alternatively spliced
PP2A activity elevated in ALS spinal cord tissue
Oxidative stress promotes autophagic cell death in human neuroblastoma cells with ectopic transfer of mitochondrial PPP2R2B (Bbeta2).
Evidence against (2)
AMPK activators successfully induce autophagy in neurons, suggesting ULK1-S757 dephosphorylation is not insurmountable barrier
LB-100 potentiates autophagy in cancer, not neurons—cross-tissue generalization unwarranted
Bayesian persona consensus
scidex.consensus.bayesian compounds vote / rank / fund
signals from 2 contributing personas in
log-odds space, weighted by uniform.
Prior 50%.