GAD glutamic acid decarboxylase

If a substance is to be a NT it should be possible to demonstrate appropriate enzymes for its synthesis from a precursor at its site of action, although peptides are transported to their sites of location and action after synthesis in the axon or distal neuronal cell body. The specificity of any enzyme system must also be established, especially if they are to be modified to manipulate the levels of a particular NT, or used as markers for it. Thus choline acetyltransferase (ChAT) may be taken as indicative of ACh and glutamic acid decarboxylase (GAD) of GABA but some of the synthesising enzymes for the monoamines lack such specificity. 

This situation is largely due to the rise of type 2 DM which now accounts for 85-90% of all cases of DM type 1 DM in which antibodies directed at the enzyme glutamic acid decarboxylase (GAD) attack and destroy the insulin-producing (3 cells... 

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g., hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine (4.166). All of these compounds cause seizures and convulsions because they decrease the concentration of GABA. 

In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (543). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. 

Two main gene therapy strategies have been intensively studied for the preven-tion of autoimmune diabetes. One is to suppress the expression of autoantigen in islet / -cells, and the other is to use immune suppression cytokines. Glutamic acid decarboxylase (GAD) has been shown to be the most important autoantigen and thus suppression of the GAD expression can treat diabetes (Yoon et al., 1999). For cytokine gene therapy, IL-4 and IL-10 have been the most widely explored. 

Figure 1(13 Chromatograms of the reaction mixture of (A) crude brain extract under glutamic acid decarboxylase (GAD) assay conditions 0.17 mg of crude enzyme protein plus assay mixture was incubated for 1 hour (B) Crude retinal extract under GAD assay conditions 0.30 mg of crude enzyme protein plus assay mixture was incubated for 2 hours. (From Pahuja et al., 1981.)...

Reetz A, Solimena M, Matteoli M, et al. (1991) GABA and pancreatic beta-cells colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion. In EMBOJ. 10 1275-84. 

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