Characterization of NPC1-I1061T proteostasis machinery for development of NPC therapeutics

PI: Andrew P. Lieberman, MD

Institution: University of Michigan Medical School

MDBR Statistics

Institutions Awarded


Countries Awarded


# of Awards


Total Amount


Of all the mutations in the NPC1 gene that cause Niemann-Pick type C1 disease, one mutation is particularly common. This mutant protein fails to fold properly and is rapidly degraded inside cells. Here we sought to define how this happens in hopes that slowing this disposal process might help recover functional protein. We discovered that the mutant protein is degraded in a complementary fashion by two pathways. One of these pathways was previously unknown to play a role in degrading mutant NPC1 protein. Our work shows that mutant NPC1 is the first well-characterized substrate for this degradation pathway, which is known as ER-phagy (short for endoplasmic reticulum selective autophagy). A few critical components of the second degradation pathway have been identified in which NPC1 is targeted to the proteasome, but many components remain to be defined. Our work suggests that slowing degradation while promoting proper folding of the mutant protein might help recover function in cells expressing this common NPC1 mutant.