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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS035181-04S1
Application #
6322007
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Fureman, Brandy E
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$25,000
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Nasertorabi, Fariborz; Alonso, Andres; Rogers, Scott W et al. (2005) Crystallization of the SH2-binding site of p130Cas in complex with Lck, a Src-family kinase. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:174-7
Carlson, Noel G (2003) Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid. J Neurosci Res 71:79-88
Meyer, Erin L; Strutz, Nathalie; Gahring, Lorise C et al. (2003) Glutamate receptor subunit 3 is modified by site-specific limited proteolysis including cleavage by gamma-secretase. J Biol Chem 278:23786-96
Meyer, Erin L; Gahring, Lorise C; Rogers, Scott W (2002) Nicotine preconditioning antagonizes activity-dependent caspase proteolysis of a glutamate receptor. J Biol Chem 277:10869-75
Gahring, Lorise C; Rogers, Scott W (2002) Autoimmunity to glutamate receptors in the central nervous system. Crit Rev Immunol 22:295-316
Leibold, E A; Gahring, L C; Rogers, S W (2001) Immunolocalization of iron regulatory protein expression in the murine central nervous system. Histochem Cell Biol 115:195-203
Gahring, L; Carlson, N G; Meyer, E L et al. (2001) Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation. J Immunol 166:1433-8
Carlson, N G; Gahring, L C; Rogers, S W (2001) Identification of the amino acids on a neuronal glutamate receptor recognized by an autoantibody from a patient with paraneoplastic syndrome. J Neurosci Res 63:480-5
Rogers, S W; Gregori, N Z; Carlson, N et al. (2001) Neuronal nicotinic acetylcholine receptor expression by O2A/oligodendrocyte progenitor cells. Glia 33:306-13
Carlson, N G; Howard, J; Gahring, L C et al. (2000) RNA editing (Q/R site) and flop/flip splicing of AMPA receptor transcripts in young and old brains. Neurobiol Aging 21:599-606

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