Progress Made toward Understanding Rare Neurological Condition

    A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms.

    Investigators at the University of Wisconsin–Madison (UW) have just published findings that shed some interesting light on a rare and fatal neurological disorder with no known cure, called Alexander disease. The results from this crucial new study were published recently in the Journal of Biological Chemistry in an article entitled “Glial Fibrillary Acidic Protein Exhibits Altered Turnover Kinetics in a Mouse Model of Alexander Disease.”

    Alexander disease belongs to a group of disorders, called leukodystrophies that involve the destruction of myelin. The disorder typically presents before age 2. Signs and symptoms of this infantile form typically include an enlarged brain and head size (megalencephaly), seizures, stiffness in the arms and/or legs (spasticity), intellectual disability, and developmental delay. Less frequently, onset occurs later in childhood (juvenile form) or adulthood.

    Using a mouse model of this disease, the research team found that a protein behind the symptoms of the disease, called glial fibrillary acidic protein (GFAP), is broken down more rapidly in the body than researchers previously found in cell culture studies. This was a significant finding since “the popular idea was that the GFAP protein would not be degraded as quickly,” explained lead study author Laura Moody, Ph.D., a former postdoctoral researcher at UW. “But nobody had really tested this idea.”

    Scientists were already aware that GFAP accumulates to excess in astrocytes, leading to the loss of motor and cognitive functions in people with the disease—and in some cases even death. However, they previously assumed its accumulation was a result of the cells creating too much protein and not breaking enough of it down. The UW team’s new findings could change the way researchers think about and try to solve Alexander disease.

    “This study is an essential foundation for figuring out how to reduce or prevent GFAP accumulation in cells,” noted senior study investigator Albee Messing, V.M.D., Ph.D., professor of neuropathology and director of the UW Waisman Center. “Previously, we thought that decreasing synthesis or increasing degradation of GFAP would be the way to go. But now it appears as if the cells have already tried to adapt to the higher levels of GFAP by increasing degradation, so we can now focus on finding ways to decrease GFAP synthesis.”

    In the study, the investigators calculated the rate at which GFAP protein was being made and degraded in mice with or without Alexander disease mutations. They fed the mice food that contained known quantities of two different versions, or isotopes, of nitrogen, a component of all proteins. The two isotopes—one heavy and one light—are not radioactive and don’t harm the animals.

    Since the heavy isotope of nitrogen occurs very rarely in nature, it makes up only a minute fraction of proteins. But the mice were fed food containing higher-than-normal levels of the heavy isotope so that when the mice ate this food, their bodies absorbed the nitrogen isotopes and used it for several purposes, including to make GFAP molecules. Using mass spectrometry to track the increase of heavy nitrogen in GFAP protein within the mice, the scientists were able to calculate how quickly GFAP was being made and degraded or turned over in cells.

    “We found that in tissue culture there was no difference in how quickly GFAP was being turned over,” Dr. Moody remarked. “But surprisingly, in the animal models, GFAP was turning over more quickly in animals with Alexander disease mutations than in ones without those mutations.”

    While not a direct measure of protein degradation, the increased rate of GFAP turnover in mouse models of Alexander disease strongly indicates that degradation is, in fact, increasing as well. The UW team believes that their new findings will change the way therapeutics for Alexander disease are devised.

    “Now that we know that GFAP is being synthesized and degraded more quickly in Alexander disease, it opens up new avenues for research,” Dr. Moody concluded. “It seems that if we can slow down the synthesis of GFAP, we should also be able to slow down its accumulation and develop therapies to treat Alexander disease.”