Interaction of nervous system proteins help researchers better understand age-related memory and hearing loss

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.