Epilepsy, Regulation of Brain Energy Metabolism and Neurotransmission

Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å ) and in complex with its allosteric activator AMP (3.4 Å ). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen.

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“…Additionally, these new structural insights may enable isozyme-specific rational drug design for therapeutic development (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Insights into Brain Glycogen Metabolism

Mathieu

Sierra-Gallay

Duval

et al. 2016

Journal of Biological Chemistry

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“…gluconeogenesis has indeed been demonstrated using aspartate, glutamate, alanine, and lactate as precursors [73][74][75][76]. Interestingly, de novo synthesis and accumulation of brain glycogen induced by methionine sulfoximine has been found to be mediated by the activation of FBPase [77]. It would be interesting to examine under what circumstances the intringuing possibility could be realized that astrocytes switch from glycolysis/glycogenolysis to gluconeogenesis.…”

Section: Relevance Of Gluconeogenesis For Glycogen Metabolism In Astrmentioning

confidence: 99%

Why does the brain (not) have glycogen?

2011

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In the present paper we formulate the hypothesis that brain glycogen is a critical determinant in the modulation of carbohydrate supply at the cellular level. Specifically, we propose that mobilization of astrocytic glycogen after an increase in AMP levels during enhanced neuronal activity controls the concentration of glucose phosphates in astrocytes. This would result in modulation of glucose phosphorylation by hexokinase and upstream cell glucose uptake. This mechanism would favor glucose channeling to activated neurons, supplementing the already rich neuron-astrocyte metabolic and functional partnership with important implications for the energy compounds used to sustain neuronal activity. The hypothesis is based on recent modeling evidence suggesting that rapid glycogen breakdown can profoundly alter the short-term kinetics of glucose delivery to neurons and astrocytes. It is also based on review of the literature relevant to glycogen metabolism during physiological brain activity, with an emphasis on the metabolic pathways identifying both the origin and the fate of this glucose reserve.

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“…This enhancement of energetic recruitment during seizure activity is so evident that it constitutes a signature of brain imaging techniques aimed at locating epileptic foci [22]. There is clear evidence that epileptic conditions are accompanied by marked metabolic adaptation [23,24]. Also, there is (surprisingly) old evidence (first reported last century in the 20's, [25]) that fasting or ketogenic diets (which can be viewed as a controlled form of dietetic fasting [26]) can control seizure activity [27][28][29], being at least as effective as anti-epileptic drugs [30].…”

Section: B Seizures and Epilepsy -Is Primary Metabolism Imbalance Imentioning

confidence: 99%

Role of The Purinergic Neuromodulation System in Epilepsy

Tomé¹,

Silva²,

Cunha³

2010

TONEURJ

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Adenosine has long been considered an endogenous anti-epileptic compound. This concept was based on the widespread distribution of adenosine A 1 receptors (A 1 R), which are mostly located in excitatory synapses; here, A 1 R inhibit glutamate release, decrease glutamatergic responsiveness and hyperpolarise neurons. However, the combined observation that synaptic A 1 R undergo desensitisation in chronic noxious situations whereas the activation of A 1 R still prevents seizure activity suggests that the A 1 R anti-epileptic action may involve non-synaptic mechanisms. Two alternative mechanisms can be considered to explain the ability of A 1 R to control seizure activity and resulting neurodegeneration: 1) the possible role of A 1 R-mediated control of metabolism; 2) the A 1 R-mediated preconditioning involving a coordinated control of neuron-glia communication. However, purinergic modulation of seizure activity is likely to involve other systems apart from A 1 R. Thus, the blockade of adenosine A 2A receptors (A 2A R), which density increases in animal models of epilepsy, can attenuate seizure activity and prevent seizure-induced neurodegeneration. Furthermore, ATP, which is the main source of the endogenous adenosine activating A 2A R, also act as a general danger signal and may also directly control seizure activity through P 2 receptors (P 2 R). Therefore, the purinergic control of epilepsy may actually involve different parallel signalling arms, some beneficial and others deleterious, probably acting at different sites (in epileptic foci and in their neighbourhood) and at different times. It is likely that combined targeting of different purinergic receptors may be the most efficacious way to control seizure activity, its spreading and the resulting neurodegeneration.

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Epilepsy, Regulation of Brain Energy Metabolism and Neurotransmission

Cited by 59 publications

References 183 publications

Insights into Brain Glycogen Metabolism

Insights into Brain Glycogen Metabolism

Why does the brain (not) have glycogen?

Role of The Purinergic Neuromodulation System in Epilepsy

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