Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

Spodenkiewicz, Marta; Dı́ez-Fernández, Carmen; Rüfenacht, Véronique; Gemperle-Britschgi, Corinne; Häberle, Johannes

doi:10.3390/biology5040040

Cited by 51 publications

(49 citation statements)

References 112 publications

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“…Because treatment of rodents with the Glul inhibitor methionine sulfoximine induces convulsive seizures (Eid et al, 2016) and because Glul is deficient in parts of the hippocampus in patients with mesial temporal lobe epilepsy (MTLE) (Eid et al, 2004;van der Hel et al, 2005), a role for Glul in epileptogenesis has been proposed. Consistent with this idea, the few described patients suffering from congenital Glul deficiency, all had neonatal onset, severe epileptic encephalopathy (Haberle et al, 2012;Spodenkiewicz et al, 2016).…”

Section: Introductionmentioning

confidence: 73%

Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration

Zhou

Dhaher

Parent

et al. 2019

Neurochemistry International

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Glutamate-ammonia ligase (glutamine synthetase; Glul) is enriched in astrocytes and serves as the primary enzyme for ammonia detoxification and glutamate inactivation in the brain. Loss of astroglial Glul is reported in hippocampi of epileptic patients, but the mechanism by which Glul deficiency might cause disease remains elusive. Here we created a novel mouse model by selectively deleting Glul in the hippocampus and neocortex. The Glul deficient mice were born without any apparent malformations and behaved unremarkably until postnatal week three. There were reductions in tissue levels of aspartate, glutamate, glutamine and GABA and in mRNA encoding glutamate receptor subunits GRIA1 and GRIN2A as well as in the glutamate transporter proteins EAAT1 and EAAT2. Adult Glul-deficient mice developed progressive neurodegeneration and spontaneous seizures which increased in frequency with age. Importantly, progressive astrogliosis occurred before neurodegeneration and was first noted in astrocytes along cerebral blood vessels. The responses to CO-provocation were attenuated at four weeks of age and dilated microvessels were observed histologically in sclerotic areas of cKO. Thus, the abnormal glutamate metabolism observed in this model appeared to cause epilepsy by first inducing gliopathy and disrupting the neurovascular coupling.

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Section: Introductionmentioning

confidence: 73%

Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration

Zhou

Dhaher

Parent

et al. 2019

Neurochemistry International

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“…Although these results remain controversial (Anlauf and Derouiche, 2013; Jayakumar and Norenberg, 2016; Sun et al, 2017), it is of great physiological and clinical importance to identify all potential cellular and molecular components involved in the life cycle of glutamate. GS deletion from the brain results in neonatal death (He et al, 2010), and mutations in the GS gene produce severe neuropathology in humans (Häberle et al, 2012; Spodenkiewicz et al, 2016). Furthermore, glutamate dysregulation has been implicated in numerous pathological states, including epilepsy, stroke, and substance use disorders, as well as several neurodegenerative diseases (Jayakumar and Norenberg, 2016; Kalivas and Duffy, 1998; Reissner et al, 2015; Sheldon and Robinson, 2007; Spencer and Kalivas, 2017; van der Hel et al, 2005; Yuan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

et al. 2019

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SUMMARY Glutamate has been implicated in a wide range of brain pathologies and is thought to be metabolized via the astrocyte-specific enzyme glutamine synthetase (GS). We show here that oligodendrocytes, the myelinating glia of the central nervous system, also express high levels of GS in caudal regions like the midbrain and the spinal cord. Selective removal of oligodendrocyte GS in mice led to reduced brain glutamate and glutamine levels and impaired glutamatergic synaptic transmission without disrupting myelination. Furthermore, animals lacking oligodendrocyte GS displayed deficits in cocaine-induced locomotor sensitization, a behavior that is dependent on glutamatergic signaling in the midbrain. Thus, oligodendrocytes support glutamatergic transmission through the actions of GS and may represent a therapeutic target for pathological conditions related to brain glutamate dysregulation.

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“…GS1 (Fig. 1B) is 70.5% homologous to human GLUL/GS1 [11] ( Supplementary Fig. 1A) and is the prevalent form expressed in neurons [12].…”

Section: Gs1 Rescues Neuronal Death Induced By Expression Of Httex1-qmentioning

confidence: 99%

Glutamine Synthetase-1 induces autophagy-lysosomal degradation of huntingtin aggregates and ameliorates animal motility in a Drosophila model for Huntington’s disease

Vernizzi

Paiardi²,

Licata³

et al. 2019

Preprint

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Glutamine Synthetase1 (GS1) is an enzyme that catalyzes the ATP-dependent synthesis of Lglutamine from L-glutamate and ammonia as a key element of the glutamate glutamine cycle, a complex physiological process occurring between glia and neurons, necessary to control the homeostasis of glutamate. Using a Drosophila model for Huntington's disease, we report that expression of GS1 in neurons ameliorates the motility defects of animals expressing the mutant Httex1-Q93 form of the huntingtin gene. At the cellular level, expression of GS1 increases the basal level of autophagy and significantly reduces the size of the toxic Htt-Q93 protein aggregates. In addition, we found that expression of GS1 prevents TOR localization at the lysosomal membrane and reduction in the phosphorylation of its effector S6K. This study reveals a novel function for GS1 in neurons linking its activity to the inhibition of TOR signaling and autophagy. The identification of novel pharmacological regulators of autophagy is of particular interest considering its beneficial role in controlling neuronal health and counteracting the detrimental effects of toxic aggregates of proteinopathies including Huntington's disease.this cycle there are Glutamine Synthetase 1 (GS1) and Glutamate Dehydrogenase (GDH). In humans, GS1 is encoded by the glutamate ammonia-ligase gene (GLUL) that converts glutamate and ATP to glutamine, and GLUD that encodes GDH that catalyzes the reversible conversion of glutamate to alpha-ketoglutarate and ammonia. [9]. In humans, mutations in the GLUL gene are associated with a severe autosomal recessive disorder resulting in encephalopathy, organ failure and severe birth defects, probably due to the inability to detoxify ammonia [10]. Drosophila contains two distinct genes encoding glutamine synthetase: GS1 and GS2, with GS1 being 70.5% homologous to human GLUL [11] and causing embryonic lethality when mutated [12]. W hile the positive role of autophagy in the pathophysiology of HD is evident [2,13], much less is known about the role of the GGC in this process. Evidences supporting the relevance of these enzymes in HD show that GS1 activity is reduced in brains from HD patients [14-17], while gain of function of GDH mutations were shown in rare polymorphisms, to favor the onset of NDDs including Parkinson and HD [18].In order to investigate the contribute of GS1 to HD, we induced its expression using a Drosophila model for HD, where the expression in neurons of exon 1 of the human HTT gene containing 93 CAG repeats (hereon referred to as Httex1-Q93) recapitulates some of the cellular and molecular events described in HD patients, including loss of neurons and animal motility [19]. Our experiments show that the ectopic expression in neurons of a functional GS1 enzyme, along with Httex1-Q93, significantly improves animal motility and rescues neuronal loss caused by Httex1-Q93 expression.At the cellular level, we found that expression of GS1 considerably decreases the size of Htt-Q93 protein aggregates in neurons, a process that is a...

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Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

Cited by 51 publications

References 112 publications

Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration

Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

Glutamine Synthetase-1 induces autophagy-lysosomal degradation of huntingtin aggregates and ameliorates animal motility in a Drosophila model for Huntington’s disease

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