GAD Enzyme Deficiency

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What is the GAD Enzyme?

Enzymes are catalysts that regulate chemical reactions in the body. The acronym GAD stands for Glutamic Acid Decarboxylase. It is an important enzyme in the body that is responsible for the irreversible conversion of Glutamic acid, an excitatory neurotransmitter to γ-aminobutyric acid (GABA).

GABA is an essential inhibitory neurotransmitter that modulates the activity of the brain cells. In the brain cells, neurotransmitters serve as chemical substances that facilitate the transmission of electric signals. These signals could either stimulate or inhibit the activity of the neurons.

A balance between excitatory and inhibitory signals is required for the optimal functioning of the brain. Hence, the GAD enzyme is vital in synthesizing the main inhibitory neurotransmitter that helps maintain this balance.

GAD Isoforms

The GAD enzyme has two isoforms – namely, GAD67 and GAD65. The GAD67 isoform is found in the cell cytoplasm and is always active, producing the GABA neurotransmitter.

On the other hand, GAD67 is found on the cell membrane and is mainly found in an inactive form called Apo-GAD65. However, in certain conditions, such as stress, it is converted to its active form for the production of GABA. The GAD enzyme is found in the neurons and the insulin-producing cells of the pancreas.

The exact function of the GAD enzyme in the pancreas is still unclear. However, it is hypothesized that it controls the release of hormones in the pancreatic cells. There are also theories that GABA produced by GAD may work to inhibit the release of insulin from the pancreas.

Functions of the GAD enzyme

As stated earlier, the GAD enzyme catalyzes a strong reaction that results in the formation of GABA. GABA is the most abundant inhibitory neurotransmitter in the human body. It has a ‘calming’ effect on the brain, such that medications that promote the activity of GABA are used to treat anxiety, sleep disorders, and chronic pain.

Also, in conditions where the activity of GABA is suppressed, certain disease conditions like epilepsy may emerge. This emphasizes the key role of the GAD enzyme.

GAD65 also attaches to the membrane of neurons and serves as an attachment site to ensure that the synthesized GABA is transported to the site of action – the nerve terminals.

Gad enzyme deficiency results in excess glutamate uptake

GAD as an Autoantigen

An autoantigen is a normal protein that has been mistakenly recognized as ‘harmful’ by the body’s immune system, making it the target of immune responses. In normal conditions, antibodies are produced by the body’s immune system to combat harmful bacteria, viruses, or fungi.

But, in autoimmune conditions, the body produces antibodies against its cells and destroys them. The GAD enzyme is an essential autoantigen in the body and has been involved in the development of several autoimmune conditions.

Autoantibodies against the GAD enzyme inhibit its function and block the production and release of the GABA neurotransmitter. Consequently, the neurons are left in a continuous excitatory state.

The damaging effect has been associated with several neurological conditions, such as stiff person syndrome (SPS), cerebellar ataxia, brainstem encephalitis, Miller-Fisher syndrome, and epilepsy. The GAD antibodies also trigger the release of inflammatory substances, which have been shown to damage nerve cells.

The presence of the GAD65 enzyme in the insulin-producing cells of the pancreas is also an antigenic target for the production of autoantibodies.

The GAD enzyme is a major autoantigen for autoimmune diabetes as elevated levels of GAD65 antibodies have been found in up to 80% of individuals with Type 1 diabetes mellitus, even before the symptoms of the disease manifest. GAD antibodies are also closely associated with Latent autoimmune diabetes in adults (LADA).

Though the exact mechanism by which antibodies to the GAD enzyme cause diabetes is yet to be fully understood, it is postulated that inflammatory responses engendered by the antibodies lead to the destruction of the insulin-producing cells (beta cells) of the pancreas. The insulin deficiency which subsequently ensues results in diabetes.

Clinical relevance

GAD Immunotherapy: Research carried out on animal subjects has shown that therapy with exogenous GAD65 enzyme can stop the destruction of the insulin-producing cells of the pancreas. This implies that administering this enzyme to patients may initiate a phenomenon called ‘immune tolerance’ and help the body to halt its attack on the beta cells of the pancreas.

A GAD vaccine with Aluminium salts incorporated into it is currently undergoing clinical trials for use in humans. Aluminum salts facilitate the recognition of autoantigens by the immune cells. Some of the studies have shown both the efficacy and safety of the GAD enzyme in preventing beta cell destruction. More studies are still underway.

Individuals with a family history of diabetes may be screened for GAD antibodies early in life, and prompt treatment with the GAD enzyme may preserve the beta cells and retain insulin function. This can be highly instrumental in averting the complications of diabetes.

Take home points

  • The GAD enzyme catalyzes a strong reaction that results in the formation of GABA, the primary inhibitory neurotransmitter in the body.
  • The GAD65 isoform is recognized as an autoantigen against which autoantibodies could be produced.
  • GAD antibodies have been associated with Type 1 diabetes mellitus and some neurological conditions.
  • Administering the GAD enzyme to patients can create immune tolerance and prevent the destruction of the insulin-producing cells of the pancreas.

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References

Fenalti G, Buckle AM. Structural biology of the GAD autoantigen. Autoimmun Rev. 2010 Jan;9(3):148-52. doi: 10.1016/j.autrev.2009.05.003. Epub 2009 May 22.

Roth FC, Draguhn A. GABA metabolism and transport: effects on synaptic efficacy. Neural Plast. 2012;2012:805830. doi: 10.1155/2012/805830. Epub 2012 Feb 23

Gresa-Arribas N, Ariño H, Martínez-Hernández E, Petit-Pedrol M, Sabater L, Saiz A, Dalmau J, Graus F. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS One. 2015 Mar 16;10(3):e0121364. doi: 10.1371/journal.pone.0121364.

Ludvigsson J; Linköping Diabetes Immune Intervention Study Group. The role of immunomodulation therapy in autoimmune diabetes. J Diabetes Sci Technol. 2009 Mar 1;3(2):320-30.

ClinicalTrials.gov [Internet] Effects of Recombinant Human Glutamic Acid Decarboxylase on the Progression of Type 1 Diabetes in New Onset Subjects (TN08) Identifier NCT00529399. [Cited Nov. 10, 2022] Available from: Effects of Recombinant Human Glutamic Acid Decarboxylase on the Progression of Type 1 Diabetes in New Onset Subjects - Full Text View - ClinicalTrials.gov

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