Mutated Gene Causes Death Of Nerves In Brain; Identification Of First Glutamate Receptor Linked With Neurodegeneration

August 20, 1997

P>A gene responsible for the degeneration and death of certain nerve cells in the brain has been cloned, yielding information that may be useful for further studies of such neurodegenerative diseases as Alzheimer's and Parkinson's, investigators from the Howard Hughes Medical Institute at The Rockefeller University and from The Johns Hopkins School of Medicine report in the Aug. 21 Nature.

The gene carries instructions to make a receptor for chemicals called neurotransmitters, which nerve cells use to communicate. The discovery, from mouse studies, marks the first time scientists have identified and directly linked a mutant gene in the glutamate receptor family to the death of brain cells. Because of the mutation, the resulting faulty receptor acts as if a neurotransmitter always is present--even when none of the chemical is there. This false detection causes the nerve cells to die.

"The mutations in the d2 glutamate receptor gene may play a role in changing the metabolism of the adult nerve cells to reactivate a program of cell death that normally occurs only during natal development. If we can reveal more about this process and understand it, it may be possible to slow the process down or stop it and preserve the neuron," explains Nathaniel Heintz, Ph.D., professor and head of the Laboratory of Molecular Biology at Rockefeller and an investigator at Howard Hughes.

During fetal development, programmed cell death is used to sculpt the final number of cells in the mature brain. About twice as many cells begin the process of developing into brain nerves than are needed in an adult brain. Consequently, many of the cells activate a biochemical program to commit suicide, known as an apoptotic death, because they receive certain chemical signals.

"We think that the surveillance mechanisms that monitor the normal metabolism of neurons are much like those monitoring the cell-division cycle in other types of cells. In neurodegenerative diseases, these mechanisms may activate the apoptotic cell death pathway as a normal response to the severe dysfunction of neurons. Our discovery of the d2 glutamate receptor gene mutation helps us to understand how this gene functions in normal neurons, but the $64,000 question remains: 'How does its altered function trigger cell death?'" says Heintz.

Heintz and his colleagues would like to pursue studies of two possible explanations related to the mutant receptor's function and the initiation of cell death. The glutamate receptor is part of a biochemical relay system that transports signals between cells. When glutamate binds to the receptor, located in the outer membrane of the neuron, the receptor allows charged molecules, usually calcium ions, to enter the cell and pass the signal along.

The first possibility of how the mutation causes cell suicide is simply that death ensues from the direct action of the receptor increasing the amount of ions coming into the cell. Other studies have shown that unusually high levels of calcium ions can enter the cell in response to increased activation of glutamate receptors, as occurs in stroke. These ions are critical in causing cell death. However, no direct pathway linking calcium ions to programmed death has yet been discovered. The second possibility is that the mutation alters the signaling properties of the receptor, and that the resulting aberrant signals are critical in the initiation of cell death.

The receptor mutation occurs because of the substitution of two of the four nucleic acids used to build the gene, located on chromosome 6 of lurcher (Lc) mice. This switch changes the instructions carried by the gene and consequently, the receptor protein it makes. The mutation causes the death of Purkinje neurons in the cerebellum, the brain structure that controls all aspects of coordination and fine motor control in mature animals.

Heintz's coauthors included Jian Zuo, Philip L. De Jager, Weining Jiang, Ph.D., at Rockefeller, and Kanji A. Takahashi and David J. Linden, Ph.D., at Johns Hopkins. The National Institute for General Medical Sciences, part of the federal government's National Institutes of Health, funded the research, with support from the National Institute of Mental Health, the McKnight Foundation, the Derelbiss Fund and the National Alliance for Research on Schizophrenia and Depression.

Rockefeller began in 1901 as the Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Recently, the university created five centers to foster collaborations among scientists to pursue investigations of Alzheimer's Disease, of biochemistry and structural biology, of human genetics, of sensory neurosciences and of the links between physics and biology.
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