Glial fibrillary acidic protein (GFAP) is an intermediate filament protein found almost exclusively in astrocytes. Our laboratory has recently shown that mutations in the coding region of the GFAP gene are associated with Alexander disease, a rare but usually fatal disorder of the central nervous system. This disease is characterized by the presence of protein aggregates which have GFAP as a primary constituent. Alexander disease has different clinical features depending on whether it presents in an infant, juvenile or adult, so it has been unclear whether it is a single disease or a family of diseases. Our previous work analyzed a sufficient number of infantile samples to suggest that GFAP mutations are responsible for many cases of this type.
Specific Aim 1 of this proposal addresses the extent to which GFAP mutations are responsible for the juvenile and adult forms. It also seeks to discover if additional, novel, mutations might be found for infantile cases. An immediate clinical benefit of the results will be more efficient, less-invasive diagnosis of Alexander disease, and fetal testing for families for families who have previously had an affected child.
In Specific Aim 2 the discovered mutations will be incorporated into expression vectors and transgenes so that their properties can be studied.
In Specific Aim 3 some of the properties of the mutated form of GFAP will be examined that might account for its toxicity; it will be determined if the protein is preferentially incorporated into the protein aggregates, whether it is more stable than the wild type GFAP, and whether it is aberrantly phosphorylated.
In Specific Aim 4 we seek to develop antibodies that will interact specifically with the mutant from the normal one. In addition to greater understanding of Alexander disease, these studies may provide insights into other protein aggregate disorders, like Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and cirrhosis of the liver.
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