Missing signal causes misrouting in certain degenerative eye diseases

05/12/04

Misplaced protein may be linked to macular degenerations

ANN ARBOR, Mich. – While scientists race to identify disease-causing genes, they know that the long-anticipated gene therapies will not be possible unless they learn more about how genes function at the cellular level.

In the April issue of Genomics, University of Michigan Kellogg Eye Center scientists provide significant details on the functioning of one gene -- and the related proteins – responsible for rare forms of macular degeneration.

In 2001, Radha Ayyagari, Ph.D., and colleagues identified the gene ELOVL4 (elongation of very-long chain fatty acids 4), associated with a severe retinal condition: autosomal dominant atrophic macular degeneration (adMD) or Stargardt-like macular degeneration. The disease affects the central part of the retina and results in loss of central vision needed for such activities as reading and driving. In the Genomics paper, Ayyagari focuses on the movement of the protein that carries out the gene's instructions.

According to Ayyagari, it appears that a key signal, one that directs the protein to the proper location within the cell, is missing in the mutated gene. In healthy cells, the protein travels between two locations, the Golgi and the endoplasmic reticulum (ER).

When the ER retrieval signal is not functioning properly, the protein accumulates in the wrong site, either in the Golgi or another cellular compartment. Ayyagari observes, "If we gain more information about the misrouting of this protein, we may learn how and why the genetic mutation causes degeneration of the macula. And that will bring us closer to interventions and treatment options."

Ayyagari adds that a similar pattern, known as defective protein trafficking, has been associated with several other retinal diseases, such as retinitis pigmentosa. While here, too, the mutation is connected to degeneration of the macula, the missing piece involves the function of the gene. "What is the role of this protein in cellular pathways?" asks Ayyagari, adding that this information would provide valuable insight into the disease.

Ayyagari observes that the cause of the degenerative disease appears to be either the lack of sufficient healthy protein or the presence of abnormal protein. She explains that once you understand the underlying problem, you can choose whether to add healthy genes or remove the product of the defective gene. With this understanding, scientists can begin to develop new treatments.

The unique composition of the retina also hints at the importance of the gene ELOVL4 in retinal degeneration. The retinal cells are composed of high levels of long-chain fatty acids, which must be maintained if the retina is to remain healthy.

"Our current research suggests that the gene is involved in the metabolism of these fatty acids, but we don't know exactly how," says Ayyagari." She plans further research aimed at learning more about the biological function of the gene, which may provide a direct link between fatty acid metabolism and the degeneration of retinal cells.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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