Finding May Help Prevent Vision Loss in Tumor Disorder
Normal brain and body nerve cells are shown on the left; body nerve cells are pictured in blue, while brain nerve cells are shown in green. When levels of the key protein are reduced, as in the cells pictured on the right, the branches of the body's nerve cells get longer, but the brain nerve cell's branches get shorter.
April 28, 2010 – Nerve cells in the body and brain cells react in opposite ways to the loss of a protein linked to a childhood tumor syndrome, researchers at Washington University School of Medicine and the Siteman Cancer Center have found.
The finding could be important to efforts to preserve the vision of patients with neurofibromatosis 1, a genetic condition that increases risk of benign and malignant brain tumors.
This condition is caused by mutations in the Neurofibromatosis 1 (NF1) gene. Other researchers had shown years ago that disabling NF1 in nerve cells from the peripheral nervous system (i.e., anywhere but the spinal cord or the brain) causes those cells to survive better and grow longer branches.
The new study, published in The Journal of Neuroscience, shows the opposite is true in brain nerve cells: Disable a copy of the NF1 gene, and the nerve cell’s branches are shorter and it is quicker to die when stressed.
"Using drugs or other treatments that successfully shrink tumors doesn't always restore vision loss in neurofibromatosis 1 patients, and we had wondered why that was the case," says senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology. "Now we know that it's because the mutation that causes the disease also makes brain nerve cells more vulnerable to the stress caused by tumors."
In a mouse model of neurofibromatosis-1 brain tumors, Gutmann's lab previously had found that some of the nerve cells affected by these tumors died. But because of earlier results that showed disabling the NF1 gene made nerve cells more likely to survive, they assumed the increased vulnerability seen in the disease came from some source other than the mutated NF1 gene.
Jacquelyn A. Brown, PhD, postdoctoral research fellow in Gutmann’s laboratory, led the new study, which began with petri dish studies of brain nerve cells known as retinal ganglion cells from their NF1 mouse model.
Because these mice have one defective copy of the NF1 gene, similar to children with neurofibromatosis 1, the cells make fewer copies of the gene's protein, neurofibromin. Brown studied retinal ganglion cells because they are the nerve cells that carry vision and are injured when children with neurofibromatosis 1 develop tumors of the optic nerve.
Her results showed that, unlike peripheral nerve cells, retinal ganglion neurons with less neurofibromin had shorter branches and died more often when stressed. She repeated the experiment with nerve cells from another part of the brain, the hippocampus, and found that those cells also were more vulnerable and had shorter branches. A nerve cell's ability to grow and maintain long branches is essential to its ability to establish healthy connections with other nerve cells.
When Brown examined peripheral nervous system cells taken from the same mice, they were nearly identical to normal nerve cells.
In additional experiments, Brown showed that reduced levels of neurofibromin affected a different biochemical pathway in brain nerve cells than in peripheral nerve cells. In brain nerve cells, reduced neurofibromin leads to less of a molecule known as cyclic AMP.
When Brown boosted brain nerve cell levels of cyclic AMP in the NF1 mouse model and let the mice develop tumors of the optic nerve as usual, fewer retinal ganglion cells died. Increasing cyclic AMP levels also reduced retinal ganglion cell death when the optic nerve was directly injured.
"There are experimental drugs now in development that boost cyclic AMP to kill cancer cells," says Gutmann, who is director of the Neurofibromatosis Center at Washington University School of Medicine. "This raises the intriguing possibility that we may be able to use the same drugs both to treat cancers and to allow more brain nerve cells to survive."
In follow-up studies, Gutmann and his team are trying to determine if the same causes of enhanced brain cell vulnerability underlie some of the learning and behavioral deficits seen in his lab's neurofibromatosis 1 mouse model.
Gutmann D, Brown J, Gianino S. Defective cyclic AMP generation underlies the sensitivity of central nervous system neurons to neurofibromatosis-1 heterozygosity. The Journal of Neuroscience, April 21, 2010.
Funding from the National Cancer Institute, and the Bakewell Neuroimaging Core and NIH Neuroscience Blueprint Interdisciplinary Center Core Grant supported this research.