Proteins Correct Lipid Storage Disorder

A report in the June 15, 2002, issue of the Journal of Clinical Investigation describes how overexpression of these proteins can correct the imbalance in cholesterol metabolism that characterizes certain GSL storage diseases.

In the GSL storage disease Niemann-Pick disease type C (NP-C), a defect in the NPC1 protein causes free cholesterol rather than cholesterol esters to accumulate in cellular organelles such as endosomes, Golgi stacks, and lysosomes. This accumulation of cholesterol interferes with the normal routing of GSLs into the Golgi apparatus.

Investigators from the Mayo Clinic (Rochester, MN, USA) found that the normal Golgi trafficking of GSLs involves caveolae or some similar specialized membrane domain and differs from the better-known mechanism involving clathrin-coated vesicles, which is used by other endocytosed lipids and proteins. Using fluorescent lipid analogs, they discovered the involvement of two small GTP binding proteins, Rab7 and Rab9, in the clathrin-independent trafficking of GSLs. Overexpression of either protein not only restores their normal patterns of GSL trafficking in NP-C cells but also reverses their abnormal accumulation of free cholesterol.

The researchers conclude that a therapeutic approach to increase the activities of Rab7 and Rab9 could be used to restore normal lipid metabolism in sufferers of GSL storage diseases.




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