Abstract

Recent studies in our laboratory revealed that a partial deficiency of glutamate dehydrogenase (GDH) and abnormal glutamate metabolism are specific biochemical defects of a form of recessively-inherited olivopontocerebellar atrophy (OPCA). Additional studies revealed evidence for the cellular presence of two distinct forms of GDH in human leukocytes and fibroblasts as well as in rat brain. One isoenzyme, which is """"""""soluble"""""""", is heat resistant (at 47.5 C) where as the other isoenzyme, which is """"""""particulate"""""""", is heat-labile (at 47.5 C). Determination of both GDH isoenzymes in leukocytes from patients with recessive OPCA revealed complete deficiency of the heatlabile GDH. These results strongly suggest that deficiency of the heat-sensitive GDH is the actual gene defect of this form of recessive OPCA. We propose: (1) To extend the current investigations on the activity of the two GDH isoenzymes in leukocytes from patients with OPCA as well as patients with other degenerative neurological disorders to further consolidate our data on the phenotype associated with GDH deficiency. (2) To investigate whether a deficiency of the heat-sensitive GDH is also present in cultured skin fibroblasts from these patients. (3) To evaluate the activities of the two GDH isoenzymes in leukocytes and cultured skin fibroblasts from obligated heterozygotes (parents and children of GDH-deficient patients). (4) To purify the rat and human brain and liver GDH isoenzymes and to compare their properties. (5) To further characterize the GDH isoenzymes in leukocytes and fibroblasts from patients and controls and to develop improved methods for their separation. (6) To expand the current studies on systemic metabolism of glutamate in patients with GDH deficiency as well as patients with other degenerative neurological disorders. (7) To further explore the possible role of GDH-activating agents such as the branched-chain amino acids in arresting or reversing the course of the GDH-deficient neurological disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS016871-05
Application #
3397199
Study Section
Neurology A Study Section (NEUA)
Project Start
1980-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029

  Publications

Shashidharan, P; Clarke, D D; Ahmed, N et al. (1997) Nerve tissue-specific human glutamate dehydrogenase that is thermolabile and highly regulated by ADP. J Neurochem 68:1804-11
Yapijakis, C; Vassilopoulos, D; Tzagournisakis, M et al. (1995) Linkage disequilibrium between the expanded (CAG)n repeat and an allele of the adjacent (CCG)n repeat in Huntington's disease patients of Greek origin. Eur J Hum Genet 3:228-34
Tzagournissakis, M; Fesdjian, C O; Shashidharan, P et al. (1995) Stability of the Huntington disease (CAG)n repeat in a late onset form occuring on the Island of Crete. Hum Mol Genet 4:2239-43
Shashidharan, P; Michaelidis, T M; Robakis, N K et al. (1994) Novel human glutamate dehydrogenase expressed in neural and testicular tissues and encoded by an X-linked intronless gene. J Biol Chem 269:16971-6
Shashidharan, P; Huntley, G W; Meyer, T et al. (1994) Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain. Brain Res 662:245-50
Shashidharan, P; Wittenberg, I; Plaitakis, A (1994) Molecular cloning of human brain glutamate/aspartate transporter II. Biochim Biophys Acta 1191:393-6
Anagnou, N P; Seuanez, H; Modi, W et al. (1993) Chromosomal mapping of two members of the human glutamate dehydrogenase (GLUD) gene family to chromosomes 10q22.3-q23 and Xq22-q23. Hum Hered 43:351-6
Plaitakis, A; Flessas, P; Natsiou, A B et al. (1993) Glutamate dehydrogenase deficiency in cerebellar degenerations: clinical, biochemical and molecular genetic aspects. Can J Neurol Sci 20 Suppl 3:S109-16
Deloukas, P; Dauwerse, J G; Moschonas, N K et al. (1993) Three human glutamate dehydrogenase genes (GLUD1, GLUDP2, and GLUDP3) are located on chromosome 10q, but are not closely physically linked. Genomics 17:676-81
Shashidharan, P; Plaitakis, A (1993) Cloning and characterization of a glutamate transporter cDNA from human cerebellum. Biochim Biophys Acta 1216:161-4

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