Question
Does distinct phosphorylation state of p21^Cip1 predict cellular responsiveness to autophagy-inducing therapies, enabling precision stratification for mTOR-independent autophagy modulators in neurodegeneration?
Falsifiable prediction from high-scoring hypothesis (score=0.729, gene=CDKN1A). Hypothesis: Does distinct phosphorylation state of p21^Cip1 predict cellular responsiveness to autophagy-inducing therapies, enabling precision stratification for mTOR-independent autophagy modulators in neurodegeneration? Success criteria: 1. Phospho-p21^T145 (non-apoptotic) vs phospho-p21^T148 (pro-autophagy) states are distinguishable by IP-WB in patient-derived fibroblasts. 2. p21^T148 phosphorylation correlates with LC3-II/LC3-I ratio >2.0 (autophagy flux) vs <1.0 in age-matched controls. 3. Autophagy inducer (e.g., carbamazepine) increases p21^T148 signal by >40% only in cells with high baseline p-Ser/Tyr ratio. 4. Patient-derived neurons with high p21^T148 show >30% reduction in polyQ aggregates after 72h autophagy inducer treatment.