Seizing the Opportunity: O-GlcNAcylation in the Fight Against Epilepsy
By Armeen Barghi
Epilepsy, an ailment which affects 50 million people around the globe, crosses many boundaries: It can affect people of all ethnicities and socioeconomic classes, especially young children and the elderly. Epilepsy is characterized by extreme and unusual activity in the brain, resulting in involuntary bodily movement for small periods of time. This movement, commonly known as a seizure, can lead to unconsciousness and subsequent hospitalization.1
In order to treat epileptic seizures, many people take antiepileptic drugs (AEDs). These drugs function by inhibiting rapid firing of neurons in the brain to prevent the development of seizures. Although many patients benefit from these drugs, a large proportion of patients are refractory to the treatment, meaning that their epilepsy does not respond to the AEDs.
In order to crack this dilemma, researchers have turned to studying O-GlcNAcylation, a process in cell biology that has profound effects on cells’ ability to metabolize glucose.
O-GlcNAcylation is a mechanism whereby specific portions of a protein become linked to a chemical known as N-acetylglucosamine (GlcN). This chemical modification, which is catalyzed by an enzyme called O-GlcNAc transferase, is necessary for many biological processes, including embryonic development, stem cell function, and glucose metabolism. Due to its prominent role, it is no surprise that impairment of O-GlcNAc transferase is implicated in the onset of several diseases, including diseases of the brain. For example, down-regulation of O-GlcNAc transferase leads to decreased brain glucose metabolism in Alzheimer’s disease,4 and upregulation of O-GlcNAc transferase leads to learning disabilities in animal models with diabetes.5 Notably, since O-GlcNAc transferase levels are particularly high in the hippocampus—the memory center—of rodents, scientists have hypothesized that O-GlcNAc might even be responsible for the formation of new memories.
Such findings hint that O-GlcNAc plays an important role in synaptic function in animals. Since higher rates of O-GlcNAc seem to correlate with lower synaptic activity, it is reasonable to suspect that increasing O-GlcNAc levels may be a viable treatment for disorders such as epilepsy in which neuronal activity is heightened.
To study O-GlcNAc in a controlled manner, a team led by Professor Stewart at the University of Alabama took slices from the hippocampi of mice and rats. The researchers then induced seizure-like activity in the brain tissue by inhibiting the action of GABA, a neurotransmitter that normally dampens neuronal firing. To test the effect of O-GlcNAc on this tissue, the team then dosed in high levels of GlcN, giving the O-GlcNAc transferase more of its requisite starting material and producing a global increase in O-GlcNac levels. The result of this experiment was promising: Epileptic activity at specific synapses in rodent hippocampi was reduced when O-GlcNAc was increased experimentally. This novel method of “long-term synaptic depression” is an intriguing demonstration of the cascading downstream effects of just a single protein modification.
Since complex machinery underlies the dampening of the over-activation of neurons, a better understanding of the intertwining circuits in the brain is needed in order to appreciate the physiological changes that take place on a molecular level. A microscopic narrative can then be used to ponder the broader, macroscopic changes that occur in the brains of epileptic patients’. People experiencing frequent seizures not only have to deal with direct physical abnormalities but also may be more susceptible to mood disorders, cognitive decline, and anxiety that could inhibit day to day activities.7
It is imperative for further research to explore potential, yet undiscovered therapeutic models based on the current data available regarding epileptic repression in animal models. Indeed, such research may hold the key to developing a more effective drug treatment for epilepsy. Studies have shown that epileptic symptoms may worsen when conventional AEDs are removed in treatment.2 However, the results found by Stewart and colleagues illustrates a more specific biochemical mechanism for seizure formation, allowing future drug designers to evaluate more appropriate drug targets. And, while this research was performed in mouse models, these results is an important step in designing a pharmaceutical drug that can help prevent epilepsy in humans.3
References
1. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475-482.
2. Harden CL. New antiepileptic drugs. Neurology 1994;44:787-787.
3. Kaminski RM, Rogawski MA, Klitgaard H. The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments. Neurotherapeutics 2014;11:385-400.
4. Liu F, Shi J, Tanimukai H, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 2009;132:1820-1832.
5. Liu Y, Liu F, Grundke‐Iqbal I, Iqbal K, Gong CX. Brain glucose transporters, O‐GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. Journal of neurochemistry 2009;111:242-249.
6. Stewart LT, Khan AU, Wang K, et al. Acute increases in protein O-GlcNAcylation dampen epileptiform activity in hippocampus. Journal of Neuroscience 2017:0173-0116.
7. Thapar A, Kerr M, Harold G. Stress, anxiety, depression, and epilepsy: investigating the relationship between psychological factors and seizures. Epilepsy & Behavior 2009;14:134-140.
Epilepsy, an ailment which affects 50 million people around the globe, crosses many boundaries: It can affect people of all ethnicities and socioeconomic classes, especially young children and the elderly. Epilepsy is characterized by extreme and unusual activity in the brain, resulting in involuntary bodily movement for small periods of time. This movement, commonly known as a seizure, can lead to unconsciousness and subsequent hospitalization.1
In order to treat epileptic seizures, many people take antiepileptic drugs (AEDs). These drugs function by inhibiting rapid firing of neurons in the brain to prevent the development of seizures. Although many patients benefit from these drugs, a large proportion of patients are refractory to the treatment, meaning that their epilepsy does not respond to the AEDs.
In order to crack this dilemma, researchers have turned to studying O-GlcNAcylation, a process in cell biology that has profound effects on cells’ ability to metabolize glucose.
O-GlcNAcylation is a mechanism whereby specific portions of a protein become linked to a chemical known as N-acetylglucosamine (GlcN). This chemical modification, which is catalyzed by an enzyme called O-GlcNAc transferase, is necessary for many biological processes, including embryonic development, stem cell function, and glucose metabolism. Due to its prominent role, it is no surprise that impairment of O-GlcNAc transferase is implicated in the onset of several diseases, including diseases of the brain. For example, down-regulation of O-GlcNAc transferase leads to decreased brain glucose metabolism in Alzheimer’s disease,4 and upregulation of O-GlcNAc transferase leads to learning disabilities in animal models with diabetes.5 Notably, since O-GlcNAc transferase levels are particularly high in the hippocampus—the memory center—of rodents, scientists have hypothesized that O-GlcNAc might even be responsible for the formation of new memories.
Such findings hint that O-GlcNAc plays an important role in synaptic function in animals. Since higher rates of O-GlcNAc seem to correlate with lower synaptic activity, it is reasonable to suspect that increasing O-GlcNAc levels may be a viable treatment for disorders such as epilepsy in which neuronal activity is heightened.
To study O-GlcNAc in a controlled manner, a team led by Professor Stewart at the University of Alabama took slices from the hippocampi of mice and rats. The researchers then induced seizure-like activity in the brain tissue by inhibiting the action of GABA, a neurotransmitter that normally dampens neuronal firing. To test the effect of O-GlcNAc on this tissue, the team then dosed in high levels of GlcN, giving the O-GlcNAc transferase more of its requisite starting material and producing a global increase in O-GlcNac levels. The result of this experiment was promising: Epileptic activity at specific synapses in rodent hippocampi was reduced when O-GlcNAc was increased experimentally. This novel method of “long-term synaptic depression” is an intriguing demonstration of the cascading downstream effects of just a single protein modification.
Since complex machinery underlies the dampening of the over-activation of neurons, a better understanding of the intertwining circuits in the brain is needed in order to appreciate the physiological changes that take place on a molecular level. A microscopic narrative can then be used to ponder the broader, macroscopic changes that occur in the brains of epileptic patients’. People experiencing frequent seizures not only have to deal with direct physical abnormalities but also may be more susceptible to mood disorders, cognitive decline, and anxiety that could inhibit day to day activities.7
It is imperative for further research to explore potential, yet undiscovered therapeutic models based on the current data available regarding epileptic repression in animal models. Indeed, such research may hold the key to developing a more effective drug treatment for epilepsy. Studies have shown that epileptic symptoms may worsen when conventional AEDs are removed in treatment.2 However, the results found by Stewart and colleagues illustrates a more specific biochemical mechanism for seizure formation, allowing future drug designers to evaluate more appropriate drug targets. And, while this research was performed in mouse models, these results is an important step in designing a pharmaceutical drug that can help prevent epilepsy in humans.3
References
1. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475-482.
2. Harden CL. New antiepileptic drugs. Neurology 1994;44:787-787.
3. Kaminski RM, Rogawski MA, Klitgaard H. The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments. Neurotherapeutics 2014;11:385-400.
4. Liu F, Shi J, Tanimukai H, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 2009;132:1820-1832.
5. Liu Y, Liu F, Grundke‐Iqbal I, Iqbal K, Gong CX. Brain glucose transporters, O‐GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. Journal of neurochemistry 2009;111:242-249.
6. Stewart LT, Khan AU, Wang K, et al. Acute increases in protein O-GlcNAcylation dampen epileptiform activity in hippocampus. Journal of Neuroscience 2017:0173-0116.
7. Thapar A, Kerr M, Harold G. Stress, anxiety, depression, and epilepsy: investigating the relationship between psychological factors and seizures. Epilepsy & Behavior 2009;14:134-140.