This hypothesis proposes that TFEB activation serves as a therapeutic strategy for neurodegenerative diseases by enhancing autophagy-lysosome pathway function to clear pathological protein aggregates. In neurodegenerative conditions like Alzheimer's, Parkinson's, and Huntington's disease, the accumulation of misfolded proteins (amyloid-β, tau, α-synuclein, huntingtin) overwhelms cellular clearance mechanisms, leading to neuronal dysfunction and death. TFEB, as the master regulator of lysosomal biogenesis and autophagy, coordinates the expression of genes in the Coordinated Lysosomal Expression and Regulation (CLEAR) network. Under normal conditions, TFEB is phosphorylated by mTORC1 and sequestered in the cytoplasm, but upon autophagy induction or lysosomal stress, it translocates to the nucleus to upregulate autophagy-related genes including ATG genes, lysosomal enzymes, and lysosomal membrane proteins. The hypothesis posits that pharmacological or genetic activation of TFEB in affected brain regions will increase autophagosome formation, enhance lysosome biogenesis, improve autophagosome-lysosome fusion, and boost proteolytic capacity.

This hypothesis proposes that TFEB activation serves as a therapeutic strategy for neurodegenerative diseases by enhancing autophagy-lysosome pathway function to clear pathological protein aggregates. In neurodegenerative conditions like Alzheimer's, Parkinson's, and Huntington's disease, the accumulation of misfolded proteins (amyloid-β, tau, α-synuclein, huntingtin) overwhelms cellular clearance mechanisms, leading to neuronal dysfunction and death. TFEB, as the master regulator of lysosomal biogenesis and autophagy, coordinates the expression of genes in the Coordinated Lysosomal Expression and Regulation (CLEAR) network. Under normal conditions, TFEB is phosphorylated by mTORC1 and sequestered in the cytoplasm, but upon autophagy induction or lysosomal stress, it translocates to the nucleus to upregulate autophagy-related genes including ATG genes, lysosomal enzymes, and lysosomal membrane proteins. The hypothesis posits that pharmacological or genetic activation of TFEB in affected brain regions will increase autophagosome formation, enhance lysosome biogenesis, improve autophagosome-lysosome fusion, and boost proteolytic capacity. This coordinated enhancement of the autophagy-lysosome system will facilitate the clearance of disease-specific protein aggregates, reduce cellular toxicity, preserve synaptic function, and slow neurodegeneration. Evidence supporting this approach includes studies showing TFEB overexpression reduces α-synuclein aggregates in Parkinson's models and improves cognitive function in Alzheimer's disease mouse models. Small molecule TFEB activators like trehalose and specific kinase inhibitors targeting mTORC1 or other TFEB-regulatory kinases represent potential therapeutic interventions. This strategy addresses the fundamental clearance deficit underlying multiple neurodegenerative diseases.