Neiman-Pick type C (NPC) disease intrigues Alzheimer's researchers for several reasons. For one thing, the neurodegenerative disorder involves tau hyperphosphorylation. For another, the two proteins that underlie the disease, NPC1 and NPC2, are clearly critical in cholesterol homeostasis in the brain, as evidenced by the dramatic buildup of neuronal cholesterol in NPC. Since there is at least some evidence that each of the APP secretases (α, β, and γ) is affected by alterations in cholesterol trafficking or concentration, a clearer understanding of cholesterol metabolism should also be useful for the β-amyloid side of Alzheimer's research.
In an article published August 16 in PNAS Early Edition, Ta-Yuan Chang's group at Dartmouth University in Hanover, New Hampshire, in collaboration with Matthew Scott's lab in Stanford University in California, reports that NPC1 binds cholesterol directly, and that sterol-sensing domains on the protein are necessary for this union.
NPC2 is a soluble lysosomal protein that clearly binds cholesterol with high affinity (see ARF related news story). However, only some 5 percent of NPC cases are due to mutations in the NPC2 gene. The remaining 95 percent of NPC cases can be blamed on a defect in NPC1, a lysosomal-endosomal transmembrane protein. While NPC1 is generally acknowledged to help guide cholesterol to appropriate intracellular compartments, there is only a circumstantial case that it binds cholesterol directly.
First author Nobutaka Ohgami and colleagues used photoaffinity labeling of intact cells to show NPC1 binding directly to the cholesterol analog 7,7-azocholestenol. This interaction does not require the assistance of NPC2, a possibility that has been suggested by some researchers. However, this binding does require that the sterol sensing domains of NPC1 be functional, as the authors demonstrated by severely reducing the binding with several different loss-of-function mutations in these domains. This latter finding suggests to the authors the possibility that other proteins involved in cholesterol-dependent regulatory events—and which possess sterol sensing domains (e.g., HMG-Coa reductase, SCAP, PATCHED, and NPC1L1)—may also bind sterols directly.—Hakon Heimer
- Ohgami N, Ko DC, Thomas M, Scott MP, Chang CC, Chang TY. Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12473-8. PubMed.