Autophagy defects in NPC1 disease and the bypass mechanism of autophagosome maturation for restoring autophagic flux
Mutant NPC1 protein prevents cholesterol efflux from the endo-lysosomal compartments and impairs autophagosome maturation in the multi-step route due to failure in the SNARE machinery. Induction of autophagy by chemical inducers bypasses this block and restores autophagic flux via direct autophagosome–lysosome fusion. A combinatorial treatment strategy is shown with cholesterol depletion agents. The green arrows indicate therapeutic effects of autophagy induction and cholesterol depletion.