We have found high titer serum autoantibodies to neuronal glutamate receptors (GluR) in several neurological diseases including Rasmussen~s encephalitis, paraneoplastic neurodegenerative syndromes, and olivopontocerebellar atrophy. In each disease the autoantibody is specific to a GluR subunit, and it directly modulates receptor function. From these observations, we have proposed the hypothesis that antoantibodies to GluR subunits are associated with, and play a direct role in, the pathogenesis of soma neurodegenerative diseases. A significant strength of these studies is that we have identified the target of the autoantibodies and how these autoantibodies alter receptor function in a manner consistent with disease pathology. Our goal is to use these autoantibodies as unique tools to study GluR structure and identify sites on the receptor that impart functional specificity to GluRs. Also, these studies of GluR autoimmunity will contribute to our understanding or neurological disorders of unknown etiology that affect discreet regions of the brain.
In Specific Aim #1 monoclonal antibodies with modulatory effects on GluR function will be developed from patients with autoantibodies to GluRs or mice immunized with specific regions of GluR subunits. These monoclonal antibodies will be evaluated for their capacity to functionally modulate the target receptor and to study furher receptor structure as in Specific Aims #2 and #3.
In Specific Aim #2 key residues in GluR epitopes that are targets of modulaatory autoantibodies will be identified and resolved using deletion mapping and alanine scanning mutagenesis.
In Specific Aim #3 the assembled receptor targeted by anti-Glur subunit autoantibodies will be characterized using: 1) single cell RT-PCR RNA transcript analysis; and 2) measuring the GluR subunit composition. The relevance of these findings will be tested by measuring the neurotoxic effect of GluR autoantibodies on cultured cells that express GluRs of defined subunit composition.
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