What is the GAD Enzyme?
GAD enzymes, or Glutamic Acid Decarboxylase enzymes, are vital catalysts that regulate chemical reactions in the body. They are responsible for the irreversible conversion of Glutamic acid, an excitatory neurotransmitter, to γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system.
GAD enzymes play a critical role in maintaining the balance of neurotransmitters in the brain, ensuring optimal functioning and mental health.
A deficiency in these enzymes can lead to various neurological disorders, including insomnia, anxiety, depression, and chronic fatigue.
The Importance of GAD Enzymes
GAD enzyme deficiency plays a significant role in developing neurological disorders, including insomnia, anxiety, depression, and chronic fatigue.
Mold toxicity, a condition often overlooked, can also contribute to GAD enzyme deficiency and subsequent neurological problems.
GAD enzymes are essential in synthesizing GABA, the primary inhibitory neurotransmitter that helps maintain the balance between excitatory and inhibitory signals in the brain.
This balance is crucial for the brain's optimal functioning, and any disturbance can harm mental health and neurological function.
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 brain's optimal functioning. Hence, the GAD enzyme is vital in synthesizing the primary inhibitory neurotransmitter that helps maintain this balance.
GAD Enzyme Isoforms
The GAD enzyme has two isoforms - GAD65 and GAD67. GAD65 is primarily found in an inactive form called Apo-GAD65 at the nerve terminals.
It is activated under specific conditions, such as stress, to produce GABA neurotransmitters. GAD67 is found in the cell cytoplasm and is always active, producing basal levels of GABA.
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 pancreas's neurons and insulin-producing cells.
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.
Dr. Sponaugle also believes that GABA produced by GAD may work to inhibit insulin release 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 critical 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.
Mold Toxicity and GAD Enzyme Deficiency
Mold toxicity, a condition caused by exposure to toxic molds such as trichothecene, can lead to GAD enzyme deficiency and subsequent neurological disorders.
In response to trichothecene exposure, the GAD enzyme is shut down, resulting in glutamate being converted to GABA, causing a neuroexcitatory state.
Dr. Sponaugle's Experience with Mold Toxicity and GAD Enzyme Deficiency
Dr. Sponaugle, a renowned physician specializing in treating patients suffering from mold toxicity, has observed a link between mold exposure, GAD enzyme deficiency, and neurological disorders such as insomnia, anxiety, depression, and chronic fatigue.
Through his extensive experience, Dr. Sponaugle has successfully treated patients with mold toxicity, helping them overcome GAD enzyme deficiency and restore their mental health and neurological function.
GAD Enzyme Deficiency and Neurological Disorders
A deficiency in GAD enzymes can lead to reduced GABA production and an imbalance between excitatory and inhibitory neurotransmitters in the brain. This imbalance can result in a range of neurological disorders, including:
Insomnia
Insomnia, a sleep disorder characterized by difficulty falling asleep or staying asleep, can directly result from low GABA levels caused by GAD enzyme deficiency.
GABA has a calming effect on the brain and is essential for promoting relaxation and sleep. A deficiency in GAD enzymes can lead to reduced GABA levels, making it difficult for individuals to fall asleep or maintain a restful sleep.
Anxiety
Anxiety disorders like generalized anxiety disorder, panic disorder, and social anxiety disorder can also be linked to GAD enzyme deficiency.
Reduced GABA levels can result in heightened neuronal activity and an imbalance between excitatory and inhibitory neurotransmitters, leading to increased anxiety and stress.
Depression
Depression is a mood disorder characterized by persistent sadness, hopelessness, and a lack of interest in activities. GAD enzyme deficiency can contribute to depression by causing an imbalance in neurotransmitter levels, leading to mood disturbances and emotional dysregulation.
Chronic Fatigue
Chronic fatigue syndrome, a disorder characterized by extreme fatigue that any underlying medical condition cannot explain, can also be linked to GAD enzyme deficiency.
Reduced GABA levels can lead to impaired neurotransmitter balance and decreased energy levels, contributing to feelings of exhaustion and persistent fatigue.
GAD as an Autoantigen
An autoantigen is a normal protein 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 and destroys antibodies against its cells. The GAD enzyme is an essential autoantigen in the body and has been involved in developing 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 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. Elevated levels of GAD65 antibodies have been found in up to 80% of individuals with Type 1 diabetes mellitus, even before the symptoms 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 pancreas's insulin-producing cells (beta cells). This insulin deficiency subsequently ensues and results in diabetes.
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, MartÃnez-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