The major goal of this proposal is to gain further understanding of the selective neurodegenerative processes occurring in Huntington's disease (HD). The hypotheses that will be examined include 1) cerebral cortical degeneration in HD is a selective process differentially involving subsets of neurons in particular cortical areas; 2) cortical pyramidal cells projecting to the striatum (corticostriatal cells) play a role in striatal degeneration in HD; and 3) the differential expression of glutamate receptor subunits (GluR) in HD may explain the selective vulnerability of neurons. The fist specific aim of this proposal is to delineate the regional and laminar vulnerability of neurons in selected regions of the cerebral cortex using a quantitative morphometric approach. Preliminary results examining primary motor cortex have suggested that neurons in particular layers of cortex may have increased vulnerability to degeneration in HD. The information obtained will form a foundation for assessing whether connectionally or neurochemically related neurons are at particular risk in HD. The second specific aim is to characterize corticostriatal neurons in rat and monkey by combining retrograde transport studies with immunocytochemistry. Because corticostriatal neurons are the principal source of synaptic striatal glutamate and excitotoxicity may involve presynaptic mechanisms, understanding how corticostriatal neurons are effected in HD will help elucidate excitotoxicity occurring in the striatum. Thus, the ultimate goal is to develop a marker enabling the study of these neurons in cases of HD. Preliminary results in a monkey experiment suggest that antisera for a specific glutamate receptor subtype may label these neurons. The third specific aim is to assess alterations in glutamate receptor subunit expression in HD using immunoblot and immunocytochemical methods. Because different GluR may have opposing influences on the ion-gating properties of glutamate receptors, their differential expression may account for the selective vulnerability occurring in distinct cell populations in HD and may even underlie HD pathogenesis. Preliminary immunoblot results show that GluR antisera bind specifically and sensitively to their human homologs and demonstrate the feasibility of this approach. These studies will further our understanding of how cerebral cortical pathology relates to the pathogenesis and morbidity of HD, will help elucidate whether corticostriatal neurons play a role in striatal pathology, and will provide detailed information about whether the expression of GluR is related to excitotoxicity in HD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001624-05
Application #
2036398
Study Section
NST-2 Subcommittee (NST)
Program Officer
Oliver, Eugene J
Project Start
1993-01-01
Project End
1997-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Li, S H; Gutekunst, C A; Hersch, S M et al. (1998) Association of HAP1 isoforms with a unique cytoplasmic structure. J Neurochem 71:2178-85
Gutekunst, C A; Li, S H; Yi, H et al. (1998) The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. J Neurosci 18:7674-86
Li, S H; Gutekunst, C A; Hersch, S M et al. (1998) Interaction of huntingtin-associated protein with dynactin P150Glued. J Neurosci 18:1261-9
Hersch, S M; Yi, H; Heilman, C J et al. (1997) Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra. J Comp Neurol 388:211-27
Feng, Y; Gutekunst, C A; Eberhart, D E et al. (1997) Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci 17:1539-47
Levey, A I; Edmunds, S M; Hersch, S M et al. (1995) Light and electron microscopic study of m2 muscarinic acetylcholine receptor in the basal forebrain of the rat. J Comp Neurol 351:339-56
Hersch, S M; Ciliax, B J; Gutekunst, C A et al. (1995) Electron microscopic analysis of D1 and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents. J Neurosci 15:5222-37
Hersch, S M; Levey, A I (1995) Diverse pre- and post-synaptic expression of m1-m4 muscarinic receptor proteins in neurons and afferents in the rat neostriatum. Life Sci 56:931-8
Gutekunst, C A; Levey, A I; Heilman, C J et al. (1995) Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci U S A 92:8710-4
Hersch, S M; Gutekunst, C A; Rees, H D et al. (1994) Distribution of m1-m4 muscarinic receptor proteins in the rat striatum: light and electron microscopic immunocytochemistry using subtype-specific antibodies. J Neurosci 14:3351-63

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