Discovery of brain-protecting protein

Johns Hopkins researchers have discovered a novel protein that can protect brain cells by interrupting a naturally occurring "stress cascade" resulting in cell death.

Reporting in the July 16 issue of the journal Neuron, the scientists say drugs mimicking the protein, nicknamed GOSPEL, have the potential to protect brain cells against a range of neurodegenerative conditions, including stroke and Alzheimer's and Huntington's diseases.

"This work has potentially broad clinical implications," says senior author Akira Sawa, M.D., Ph.D., director of molecular psychiatry.

Sawa and his team, in collaboration with Johns Hopkins neuroscientist Solomon Snyder, M.D., and his team, conducted experiments showing that GOSPEL competes with a second protein when it tries to latch on to glyceraldehyde-3-phosphate dehydrogenase or GAPDH, a multifunctional molecule. By binding to GAPDH itself, GOSPEL both prevents the cell death cascade and offers brain cells protection against potentially toxic agents.

Sawa has spent more than a decade studying GADPH activity and its role in so-called oxidative-stress-induced cellular responses, including programmed cell death.

That cascading process begins when various stressors such as injury or disease activate a complex enzyme, nitric oxide synthase, which then forms nitric oxide, a chemical that transmits signals between nerves but also is toxic to cells. Excess levels of nitric oxide cause GAPDH to undergo a chemical modification called S-nitrosylation that in turn lets it bind to another protein called Siah1. The combined GAPDH-Siah1 molecules then move into a cell's nucleus, hijack key portions of its DNA and set off a chain of reactions leading to cell death.

In the currently reported study, the researchers analyzed tissue samples from rats to identify the DNA coding for GOSPEL (which stands for GAPDH's competitor Of Siah Protein Enhances Life) and found that the protein exists in tissues in the brain, heart, lung and skeletal muscle, though it is most widely expressed in neurons in the central nervous system.

A series of laboratory experiments in mouse brain tissue found that S-nitrosylation is necessary to enable GOSPEL to bind to GAPDH; that GOSPEL competes with Siah for GAPDH binding; that GOSPEL prevents GAPDH from slipping into the cell nucleus; and that GOSPEL diminishes brain cell damage by preventing the binding of GAPDH and Siah.

To determine whether GOSPEL's neuroprotective actions were evident in live mice, the scientists used a benign virus to deliver either GOSPEL or an altered version of GOSPEL lacking the property to bind with GAPDH into the animals' brains. They then injected a neurotransmitter, NMDA, to induce and simulate other kinds of brain damage. The researchers found that NMDA-induced lesions in the brains of mice injected with GOSPEL were about 30 percent smaller than in those injected with the altered GOSPEL, showing that the neuroprotective influence of GOSPEL related to its ability to bind to GAPDH.

The GOSPEL molecule was first available in the database of the Human Genome Project, Sawa says, but until now was designated as a genetic compound with no known properties.

The work was supported by grants from the U.S. Public Health Service, the Stanley Medical Research Institute, NARSAD (the National Alliance for Research on Schizophrenia and Depression), the CHDI Foundation, and the S-R Foundation.

Coauthors were Nilkantha Sen, Makoto R. Hara, Abdullah Shafique Ahmed, Matthew B. Cascio, Atsushi Kamiya, Jeffrey T. Ehmsen, Nishant Aggrawal, Lynda Hester, Sylvain Dore, and Solomon H. Snyder, M.D.