Niemann-Pick type C pathogenesis and treatment: from statins to sugars.

The isolation of the causative genes for Niemann-Pick type C disease, a panethnic lysosomal lipid storage disorder, has provided models of how sterols and other lipids such as glycosphingolipids traverse the membranes of eukaryotic cells. Unfortunately, these molecular advances have yet to reciprocate with a cure for this devastating neurodegenerative disorder where neuronal replenishment will most likely yield the greatest benefit. In the meantime, stabilizing treatment strategies based on the removal of presumably toxic metabolites are in place. For example, the small molecule inhibition of glucosylceramide synthase by miglustat limits ganglioside accumulation and is now the only approved treatment of Niemann-Pick type C. In addition, 2-hydroxypropyl-B-cyclodextrin, a lipid chelator, relieves the lysosomal to endoplasmic reticulum blockage and markedly increases the life expectancy of the murine model. Ultimately, these strategies, targeting the primary biochemical lesion in these cells, and others will likely be combined to provide a synergistic cocktail approach to treating this disease.