April 11, 2008

Discovery Lecture outlines novel cell-death pathway

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Solomon Snyder, M.D., talks about how his research team established that certain gases are novel neurotransmitters. (photo by Dana Johnson)

Discovery Lecture outlines novel cell-death pathway

At one point during last week's Discovery Lecture, Solomon Snyder, M.D., asked the audience if it was familiar with the tongue-twister about Peter Piper and the pickled peppers.

Snyder was joking about some of the lengthy protein names in his talk — “try saying this one five times” — but a sense of twisting, turning, and eventually mastering something complicated fit the lecture as well.

Snyder, professor of Neuroscience at The Johns Hopkins University, described how his team discovered a novel cell death signaling pathway that has implications for treating neurodegenerative diseases.

The research started with Snyder wondering if nitric oxide — at the time known to play a signaling role only in blood vessel relaxation — “did anything important in the brain.” His group's efforts to explore this question established that gases — nitric oxide and carbon monoxide — are novel neurotransmitters.

The investigators continued to explore how nitric oxide works, developing techniques to determine which proteins are “nitrosylated,” the addition of nitric oxide onto a protein.

They discovered that one nitrosylated protein was a so-called “housekeeping” protein called GAPDH that participates in metabolic pathways.

In pursuing this connection, the investigators established that nitrosylated GAPDH binds to a protein called Siah, and that this complex moves into the cell nucleus and turns on cell death pathways through another set of signaling interactions. The team has proven every step in the pathway, Snyder said.

“Understanding the mechanisms of cell death is very important for neurodegenerative diseases and strokes,” Snyder said. “If you could block cell death by interfering with cell death signaling cascades, that could be therapeutically important. You don't need to be a genius to see many molecular targets for therapeutic agents that could be developed based on this nitric oxide signaling pathway.”

The drug deprenyl, used for many years to treat Parkinson's Disease, appears to work by blocking nitrosylation of GAPDH, which came as a surprise when this mechanism was discovered, Snyder said. Other agents that protect neurons from death by interfering with the nitric oxide-GAPDH-Siah pathway are in trials, he added.

Snyder, one of the nation's pre-eminent molecular neuroscientists and a member of the National Academy of Sciences, was awarded the Albert Lasker Award for Basic Medical Research in 1978 for his pioneering work in identifying the opiate receptors.

The Discovery Lecture was sponsored by the Center for Molecular Neuroscience as the Aravind Babu Lecture in Membrane Biology, which was established to honor the memory of Babu, a Vanderbilt neuroscience graduate student who died in 2002.

For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.