Resolve: VCP/p97 ATPase mutations impair extraction of ubiquitinated autophagy substrates

Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=VCP). Hypothesis: Do VCP/p97 mutations (common in IBMPFD/ALS) impair extraction of ubiquitinated autophagy substrates, causing proteasome-autophagy flux obstruction, and does VCP activation restore this flux? Success criteria: 1. VCP mutant (A232E) iPSC neurons show >60% accumulation of ubiquitinated aggregates vs WT. 2. VCP activator (ML360) reduces ubiquitinated protein aggregates by >40% in VCP mutant neurons. 3. Autophagy flux (LC3-II/ p62 turnover) normalizes to within 20% of WT after ML360 treatment. 4. Mitochondrial function (OCR) improves by >30% in ML360-treated VCP mutant neurons.