Chinese hamster ovary cells lacking NPC1 exhibit aberrant sphingolipid and cholesterol accumulation. In the new work, the authors found that expressing NCR1, the yeast orthologue of NPC1, repairs all of the lipid transport defects in these mammalian cells. Functional conservation across a billion years of evolution is especially surprising in this case, since yeast do not engage in receptor-mediated transport of exogenous cholesterol.
Extraordinary conservation implies a critical function, but deleting NCR1 in yeast cells has no detectable effect on sterol metabolism. A dominant–negative mutation in the conserved putative sterol-sensing domain of NCR1, however, causes pronounced sphingolipid trafficking defects in yeast without affecting sterol trafficking. NCR1 and its homologues appear to share a primordial function in sphingolipid transport, and it is possible that defects in cholesterol transport in NP-C are simply a byproduct of the close association of cholesterol with sphingolipids in membrane rafts.
The lack of a phenotype in NCR1-null yeast cells also indicates that some other sphingolipid transport pathway must be able to compensate for the loss of NCR1. The authors are now trying to identify NCR1 binding proteins and to elucidate the alternate pathway, efforts that could uncover novel therapeutic targets for the treatment of NP-C. ▪