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Research reveals lipids' unexpected role in triggering death of brain cells
Date:11/12/2009

pid build up in the GEMs, said Ida Annunziata, Ph.D., a postdoctoral fellow in d'Azzo's laboratory. She shares first authorship of the paper with Renata Sano, Ph.D., a former postdoctoral fellow in d'Azzo's laboratory, currently at the Burnham Institute for Medical Research, La Jolla, Calif.

Investigators found evidence that the build-up of GM1 changes the composition of the contact sites linking ER and mitochondria and increases their number. Within the GEMs of diseased mice, researchers found elevated levels of three proteins that play important roles in transporting calcium from the ER to the mitochondria.

Those proteins include the phosphorylated form of IP3 receptor-1 (IP3R-1), which is important for the release of calcium from the ER. Not only is there more IP3R-1, but researchers reported that the protein physically interacts with GM1. d'Azzo suggested that the interaction might promote clustering of the IP3R-1 on the ER side of the GEMs, but the structural effects of accumulated GM1 on this protein must still be determined.

"It is becoming more and more apparent that intracellular organelles, including the ER, cross-talk with each other," d'Azzo said. "Here we show that in GM1-gangliosidosis, build-up of GM1 at the MAMs/GEMs alters the normal cross-talk between the ER and mitochondria."

For patients with GM1-gangliosidosis, investigators now believe problems begin when GM1 builds-up in the ER, exhausting its calcium supply and disrupting protein folding.

The second hit comes as the mitochondria struggles and eventually fails to cope with the calcium streaming in from the ER across the GEMs. Overloaded with calcium, the mitochondrial membrane becomes leaky, and a pore, known as the permeability transition pore (PTP), opens. Eventually the mitochondria release specialized proteins, like cytochrome c and other factors, triggering a biochemical cascade that ends in the destruction of both the mitochondria and the c
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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