Impaired TFEB/TFE3 Nuclear Translocation Due to mTORC1 Hyperactivity in Motor Neurons

Motor neurons exhibit constitutive mTORC1 activation that phosphorylates TFEB/TFE3 transcription factors, sequestering them in the cytoplasm and preventing transcription of autophagy-lysosomal genes. This creates a ‘locked’ state where general autophagy inducers cannot overcome mTOR-mediated repression. However, SKEPTIC critique revealed this hypothesis may conflate upstream TFEB activation with downstream execution, and that constitutive mTORC1 activity reflects physiological neuronal homeostasis rather than dysregulation. DOMAIN_EXPERT recommends performing falsification experiment with constitutively nuclear TFEB before committing resources.