A new approach for restoring defective Sonic Hedgehog signaling and autophagy in lysosomal storage and other neurodegenerative disorders

Loss-of-function mutations of Niemann Pick C1 intracellular cholesterol transporter (NPC1) cause a rare genetic condition (NPC1 disease, NPCD) in which cholesterol (Chol) and sphingolipids are entrapped in late endosomes/lysosomes and lipid raft integrity is disrupted. Sonic hedgehog (Shh) signaling, which is essential for the development of neurons and glia as well as the formation of synapses, is one of the signaling pathways impacted by this Chol dyshomeostasis. In fact, cholesteroylation and its interaction with the Patched receptor to control the Chol pool required for the activation of Smoothened and downstream effectors at the primary cilium are part of Shh activation. Interestingly, lysosomal Chol accumulation also causes mTORC1 to become hyperactive. This has been demonstrated to affect Shh signaling in cells lacking Tsc2 by mislocalizing Smoothened and lowering the concentration of Gli2 in primary cilia.