Protein is key to fatal disorder and normal cel...( n disease caused by mutations in the C...)

n disease, caused by mutations in the CLN3 gene, is the most common inherited neurodegenerative disease of childhood. Children who inherit a copy of the defective CLN3 gene from both parents produce a non-functional form of the protein. Those affected develop normally until about age five. Between the ages of five and eight years, their vision, motor and cognitive skills begin to deteriorate, with uncontrolled seizures and massive cell loss in the brain eventually resulting in death in the twenties.

Duke graduate student Dixie-Ann Persaud-Sawin, lead author of the study, focused her investigation of the protein primarily on human and rat brain cells because most of the disease's effects occur in the brain. She also studied cultured skin cells from patients, as these cells die more rapidly than their normal counterparts.

Persaud-Sawin found that the normal cln3 protein resides in the Golgi, a cellular body that packages proteins for use and transport within a cell. Cln3 also appears in complex fat platforms, or lipid rafts, within the cell surface and protective membrane coating. Time-lapse microscopy revealed that cln3 moves rapidly back and forth between the Golgi and the cell surface.

"It turns out that the cln3 protein may be a crucial protein involved in the transport of vital lipids from the Golgi, where they are made, to where they are needed -- for example, at the cell surface," Boustany said.

One of those vital lipids is galactosylceramide (GalCer). GalCer is a major constituent of lipid rafts. These lipid platforms are important for the initiation of signaling events in the cell, such as programmed cell death, or apoptosis.

The mutant cln3 protein lacks the amino acids that serve as a structural binding site for GalCer. In mutant patient cells, both cln3 and GalCer remain trapped in the Golgi and never move into the cell's plasma membrane, the Duke team discovered. With GalCer missing from the lipid platforms at the c
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Contact: Becky Oskin
Becky.oskin@duke.edu
919-684-4148
Duke University Medical Center
15-Sep-2004

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