To evaluate a putative immune response after adenoviral delivery, cytokines measure-ments should be performed at pre- and post-injection times. This should be completed by hematoxylin/eosin staining to assess the structure of the liver acini and the possible infiltration of immune cells. HepGlud1-/- Ad-hGDHS445Ldisplayed higher peripheral con-centrations of glutamate, suggesting that the predominant flux of the reaction catalysed by mutant GDH is towards glutamate synthesis. It would be interesting to investigate potential links between such higher plasma glutamate levels and epilepsy. In the brain, increased extracellular concentrations of glutamate before or during seizure onset con-tributes to their initiation [Meldrum, 1994]. To assess the differences between control mice and HepGlud1-/- Ad-hGDHS445L in epileptogenesis, we could perform pentylenetetrazole injections in escalating doses as a model revealing sensitivity to epilepsy seizures. Record-ing of the experiments would potentially provide us with important information about seizure onset, its severity and duration. This in turn might permit us to assess if higher peripheral concentrations of glutamate impact on the onset and duration of seizures in our mouse model, potentially recapitulating epileptic phenotype in HA/HA patients and the contribution of hepatic mutant GDH. If this turn to be successfully established we could combine this set up with the mouse model of GDH knock out in central nervous system. Through stereotaxic injection we could potentially deliver human mutant GDH to the region of interest in the brain. Pump with glutamate placed subcutaneously with optimized released could reach the plasma glutamate concentration from HepGlud1-/ -Ad-hGDHS445L. Thereby mimicking its phenotype: increased plasma glutamate concen-tration. Thus, we could assess if increased peripheral glutamate concentration can impact glutamate turn over in the brain and its effect on human mutant GDH in the brain.
3.5 Conclusions
More than 60 years of research has been dedicated to the understanding of the function and allosteric regulation of GDH, which sheer complexity continues to challenge and mystify scientists. Its complex tissue-specific behaviour evolved to accommodate new functions in different cell types. Its importance is witnessed by single point mutations inGLU D1 gene causing detrimental HI/HA syndrome, which case study was presented in the first paper of this thesis. It is the first molecular characterisation of G446V-GDH. This mutation af-fects complex dance between allosteric regulators and GDH, handicapping proper motion necessary for the catalytic turnover of the enzyme.
3.5. Conclusions
In our second study, we used a mouse model of liver-specific GDH knockout display-ing mild systemic hyperammonaemia. To understand metabolic consequences of hepatic GDH deletion we investigated inter-organ ammonium trafficking. We characterize changes in nitrogen metabolism based on the amount of protein consumed by investigating am-monium detoxifying systems and excretion through urine. We measured main amam-monium carriers: urea and glutamine in plasma and urine; which led us to build a comprehensive model of nitrogen metabolism based on protein consumption. Interestingly, we observed that hyperammonaemia of HepGlud1-/- mice decreased substantially with high protein intake. The standard treatment of patients suffering from elevated plasma ammonium levels consists in the limitation of protein intake. Our study may suggest an interesting alternative for patients suffering for inborn mutations affecting ammonium metabolism with functional liver.
Studies on hyperammonaemia started more than a century ago, when a Pavlov and colleagues observed in 1893 ‘meat intoxication syndrome’ on dogs with a portacaval shunt [Hahn M, 1893]. In recent years, this topic has been studied sparsely, maybe because stud-ies on ammonium pose a significant technical problem concerning the nature of ammonium itself and, as a consequence, are difficult to perform. However, in order to understand the consequences of hyperammonaemia and to develop potential therapies, such a missing knowledge would be essential. We are in the process of establishing the mouse model which could potentially address the question of source of hyperammonaemia in HI/HA patients.
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