Question
Does parallel activation of TFEB and TFE3 synergistically enhance lysosomal and mitochondrial biogenesis through the CLEAR network, providing superior proteostasis restoration vs single-TFEB approaches?
Falsifiable prediction from high-scoring hypothesis (score=0.727, gene=TFEB (TFEB), TFE3 (TFE3)). Hypothesis: Does parallel activation of TFEB and TFE3 synergistically enhance lysosomal and mitochondrial biogenesis through the CLEAR network, providing superior proteostasis restoration vs single-TFEB approaches? Success criteria: 1. Dual TFEB/TFE3 activation (via novel small-molecule or AAV-TFEB/TFE3) increases expression of >15 CLEAR network genes by >2-fold in iPSC-derived neurons. 2. Lysosomal activity (Cathepsin B/V) increases by >50% vs single-TFEB activation. 3. Mitochondrial function (OCR) improves by >30% and mitochondrial ROS decreases by >40%. 4. In neurodegeneration models: alpha-synuclein aggregation decreases by >40% vs single-TFEB or vehicle control.