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Scientists Closing In On Nerve Proteins' Contributions to Memory and Hearing Loss

St. Louis, Nov. 4, 2004 — In a finding that may one day help researchers better understand age-related memory and hearing loss, scientists have shown that two key nervous system proteins interact in a manner that helps regulate the transmission of signals in the nervous system.

Researchers report online in Nature Neuroscience that they've connected neuregulin-1 (Nrg-1), a protein linked to schizophrenia, and postsynaptic density protein-95 (PSD-95), a protein associated with Alzheimer's disease. The print version appears during the first week of November.

Nrg-1 originally caught scientists' attention because of its links to processes that encode memory in nerve cells. Scientists later found mutations in the Nrg-1 gene increased risk of schizophrenia in Scottish and Icelandic populations.

Nrg-1 is positioned in the outer membrane of nerve cells, with a portion hanging outside the nerve cell and another part jutting inside it. The exterior portion, known as Nrg-ECD, contributes to the formation of synapses, areas where two nerve cells communicate across a small physical gap, and to other aspects of nervous system development and communication.

Until recently, researchers gave little attention to Nrg-ICD, the interior portion of Nrg-1. But Jianxin Bao, Ph.D., research assistant professor of otolaryngology at Washington University and other scientists have begun amassing evidence that Nrg-ICD might be as important or even more important than Nrg-ECD.

“In a comparison of the frog and human genes, we earlier showed that Nrg-ICD was 87 percent identical between the two species,” says Bao, who is first author of the new study. “When part of a protein is kept mostly unchanged for so long over the course of evolution, it suggests that part has some very important contributions to make.”

Scientists knew that stimulation of a nerve cell causes Nrg-ECD to break off. In a previous experiment, Bao and colleagues at Columbia University found that stimulation of nerve cells in mice ears let Nrg-ICD break away from the synapse and travel to the nucleus of the nerve cell, where it blocked genes related to a cellular self-destruct process.

In the new study, researchers showed that in addition to increasing levels of Ngr-ICD, stimulation of the nerve cells caused a corresponding increase in levels of PSD-95. Normally this would lead to suspicions that Ngr-ICD was binding to DNA to increase the activity of the PSD-95 gene, but scientists already knew that Ngr-ICD can't bind to DNA on its own.

However, Ngr-ICD can bind to zinc finger proteins, which are known for their ability to bind to DNA and change the activity levels of genes. Using a technique known as an electrophoretic mobility assay study, scientists tested Ngr-ICD's ability to bind to parts of various zinc-finger proteins that they already knew could increase the activity of PSD-95. After this study and additional testing, they determined that Eos, a recently identified zinc finger protein, was Ngr-ICD's most likely partner.

In its normal role, PSD-95 provides a support structure for receptors on the receiving end of a synapse. The protein has also been detected in plaques in the brains of Alzheimer's patients.

“If you have too many receptors at a synapse, the nerve cell gets overstimulated and dies,” Bao notes. “Too few, and the signal can't get through. Adjusting this ability for a signal to get through is thought to be essential to the creation of learning and memory, so a delicate balance has to be struck in this protein's activity levels.”

Bao suspects age-related decreases in Nrg-1 levels may be linked to hearing loss and memory loss, and has begun testing mice genetically modified to make more Nrg-1 to see if they have improved hearing when they are older.

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Bao J, Lin H, Ouyang Y, Lei D, Osman A, Kim T-W, Mei L, Dai P, Ohlemiller KK, Ambron RT. Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nature Neuroscience, November 2004, pp. 1250-1258.

Funding from the National Institute on Aging.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.