GLUTAMIC DEHYDROGENASE IN NEUROLOGIC DISORDERS

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Glutamate dehydrogenase(GDH) has been shown to be significantly reduced in patients with heterogenous neurological disorders with system atrophy in which the metabolism of glutamate is abnormal. There is evidence that distinct GDH abnormalities, probably resulting from gene mutations, may underlie the clinical and genetic heterogeneity associated with reduced enzymatic activity. Thus, multiple GDH isoproteins have been shown to exist in human brain, some of which differ in their N-terminus. These were found to be differentially reduced in quantity and altered in catalytic properties and function in the brain of patients with 2 distinct types of neurodegenerative disorders. In addition, multiple mRNAs of different size have been shown to exist in various mammalian tissues, including human brain as well as multiple GDH genes. However, it is still unclear whether the different sized mRNAs and GDH isoproteins are specified by nonidentical genes or result from one functional gene by alternate splicing and post- translational modification processes,respectively. To answer these questions and further elucidate the role of the enzyme in the biology of the nervous system in health and disease, we propose: 1) To further characterize the GDH isoproteins in brain and cultured lymphocytes of patients with various degenerative neurological disorders and controls. 2) To further characterize the GDH-specific mRNAs in controls and neurologic patients and determine whether they represent distinct species. 3) To isolate and characterize GDH specific cDNA from cultured lymphocytes of neurologic patients with abnormal GDH in order to search for the gene defect responsible for the altered enzyme activity. 4) To express mutant cDNAs in heterologous cell systems in order to characterize the enzyme produced and explore causality of these mutations to human neurodegenerations. In addition, the structure, organization and function of the of the human GDH genes will be determined. These studies will lay the ground work for further analysis of the above disorders at the genomic DNA level.