TFEB-Mediated Retromer Biogenesis to Restore Endosomal-Lysosomal Trafficking in Aged Synapses

This hypothesis proposes that TFEB activation can restore synaptic function in aging by simultaneously upregulating both lysosomal biogenesis and retromer complex components, creating a coordinated enhancement of the endosomal-lysosomal trafficking network. While TFEB is well-established as a master regulator of lysosomal genes, emerging evidence suggests it also controls expression of retromer components including VPS35, VPS26, and VPS29. In aged synapses, both lysosomal capacity and retromer-mediated protein sorting are compromised, leading to accumulation of misfolded proteins, defective autophagy, and synaptic dysfunction. By pharmacologically or genetically activating TFEB, we can trigger transcriptional upregulation of the entire endosomal-lysosomal machinery as a unified system. This approach leverages TFEB’s broad transcriptional control to coordinate multiple trafficking processes rather than targeting individual components in isolation. The hypothesis predicts that TFEB activation will restore proper trafficking of critical synaptic proteins like AMPA receptors, BACE1, and APP by enhancing both the retromer sorting machinery and the downstream lysosomal degradation capacity. This coordinated enhancement should be more effective than targeting either system alone, as it addresses the interconnected nature of endosomal sorting and lysosomal processing. Testing would involve measuring retromer component expression, lysosomal biogenesis markers, and protein trafficking dynamics in aged neurons following TFEB activation, with functional readouts including synaptic protein localization, autophagy flux, and electrophysiological measures of synaptic strength.