- Research article
- Open Access
The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment
© The Author(s). 2016
- Received: 8 December 2015
- Accepted: 6 August 2016
- Published: 18 August 2016
The Erratum to this article has been published in Molecular Neurodegeneration 2017 12:4
Our previous studies of Alzheimer’s disease (AD) suggested that glutamine broadly improves cellular readiness to respond to stress and acts as a neuroprotectant both in vitro and in AD mouse models. We now expand our studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). Unlike AD, where clinically significant cognitive decline does not typically occur before age 65, A-T symptoms appear in early childhood and are caused exclusively by mutations in the ATM (A-T mutated) gene.
Genetically ATM-deficient mice and wild type littermates were maintained with or without 4 % glutamine in their drinking water for several weeks. In ATM mutants, glutamine supplementation restored serum glutamine and glucose levels and reduced body weight loss. Lost neurophysiological function assessed through the magnitude of hippocampal long term potentiation was significantly restored. Glutamine supplemented mice also showed reduced thymus pathology and, remarkably, a full one-third extension of lifespan. In vitro assays revealed that ATM-deficient cells are more sensitive to glutamine deprivation, while supra-molar glutamine (8 mM) partially rescued the reduction of BDNF expression and HDAC4 nuclear translocation of genetically mutant Atm−/− neurons. Analysis of microarray data suggested that glutamine metabolism is significantly altered in human A-T brains as well.
Glutamine is a powerful part of an organism’s internal environment. Changes in its concentrations can have a huge impact on the function of all organ systems, especially the brain. Glutamine supplementation thus bears consideration as a therapeutic strategy for the treatment of human A-T and perhaps other neurodegenerative diseases.
- Alzheimer’s disease
Glutamine (Gln or Q) is the most abundant free amino acid in the human blood stream. Normally, the body can make enough glutamine for its needs and under these conditions glutamine is a non-essential amino acid. Yet in times of stress glutamine is depleted from the blood stream faster than it can be produced in muscle and other tissues. Under these conditions, cells become dependent on an exogenous supply of glutamine. This context-dependent shift has led to the classification of glutamine as a “conditionally essential” amino acid. In the central nervous system, brain glutamine is the major substrate for the generation of both excitatory and inhibitory neurotransmitters (glutamate and γ-aminobutyric acid). It is also a vital source of energy for the nervous system as it feeds directly into the tricarboxylic acid (TCA) cycle, the main source of ATP in the cell.
We have previously shown the neuroprotective value of glutamine supplementation in vitro and in vivo . Specifically, short term oral glutamine supplementation significantly reduces the biochemical indices of neurodegeneration in mouse models of Alzheimer’s disease. The benefits of glutamine supplementation were broad spectrum and included reduction of tau phosphorylation, blockage of neuronal cell cycle reentry, improvement in the DNA damage response and a reduction in synaptic protein loss. As part of this earlier study we showed that low glutamine decreases the abundance of several key stress response proteins, including ATM (ataxia-telangiectasia mutated).
ATM deficiency, caused by mutations in the ATM gene, underlies a childhood neurodegenerative disease known as ataxia telangiectasia (A-T). Due to the loss of cerebellar Purkinje and granule cells, patients with A-T suffer from uncoordinated or ataxic movements beginning at 2–3 years of age . A-T patients also have increased mortality because of cancer, respiratory system infections, and various other rare complications. The median life-span of an individual with A-T is about 23 years . Affected individuals can also develop cardiovascular disease, accelerated aging, and insulin resistance. Systemic inflammation may contribute to these disease phenotypes as an immune challenge significantly alters the timing and severity of the A-T phenotype in Atm −/− mouse brain [4, 5]. Although there are no reports of an inflammatory reaction in their brains, A-T patients have elevated serum IL8, a pro-inflammatory CXC chemokine and neutrophil chemoattractant associated with premature cellular senescence and chronic inflammatory disorders . Notably, recent studies have suggested that glutamine plays an important role in regulating IL8 secretion; deprivation of glutamine stimulates IL8 secretion in U2OS osteosarcoma cells and A549 lung cancer cells as well as in human A-T fibroblasts [7, 8].
Beyond these immune system abnormalities, A-T children are known to have a lower body mass index and often fail to thrive [9–11]. A recent study by Ross et al. demonstrated profound malnutrition in A-T patients and the need for early nutritional intervention . These observations plus the neuroprotective effect seen in mouse models of Alzheimer’s disease led us to hypothesize that glutamine might be beneficial in A-T as well as in AD. In this study, we present multiple lines of evidence from Atm −/− mice in support of this hypothesis. We suggest that glutamine supplementation has significant potential as part of a therapeutic regimen for the treatment of A-T.
A-T mouse models
For our A-T model, we chose the Atm tm1Awb mutant allele  and the Atm tm1Bal mutant allele  from The Jackson Laboratories. All in vivo experiments were done using Atm tm1Awb strand. For primary neuron culture, both strands were used. All animal procedures were performed according to Rutgers University Institutional Animal Care and Use Committee standards.
For glutamine supplementation experiments, 4 % glutamine (Sigma) in sterile tap water was made fresh daily and offered as the sole source of drinking water for 5 consecutive days (Monday through Friday). Control mice were fed with only sterile tap water. To avoid undue stress from elevated ammonia concentrations, all mice drank glutamine-free water 2 days each week (Saturday and Sunday).
Blood glucose and glutamine measurements
About 0.3 ml blood was collected by quick sub-mandibular bleeding from mice before sacrifice. Non-fasting blood glucose concentration was measured using the Roche Accu-Chek Aviva Plus Blood Glucose Meter. For glutamine assays, blood samples were deproteinized immediately using the Deproteinizing Sample Preparation Kit from BioVision following the manufacture’s protocol. Deproteinized samples were kept in the −80° freezer before assay. Blood glutamine concentration was measured using EnzyChrom™ Glutamine Assay Kit from BioAssay Systems following the manufacturer’s protocol.
Primary neuronal cell cultures
Timed pregnancies were established from wild type ICR mice (Taconic Biosciences) or wild type mice from Atm −/− colonies. Embryos were harvested on embryonic day 15.5–16.5 for cortical neuron culture as previously described . Neurons were cultured in normal medium with 2 mM of a glutamine-alanine dipeptide (GIBCO® GlutaMAX™, Life Technologies) as a source of glutamine. Culture media were changed every 4–5 days. On DIV9–11, neurons were fed with fresh medium with different concentrations of Glutamax. 72 h later, on DIV12–14, neurons were collected for immunostaining or western blotting or gene expression analysis. To block endogenous glutamine production, neurons were treated with a combination of 5 mM glutamine synthase (GS) inhibitor methionine sulfoximine (MSO) (Sigma). Either ATM-specific inhibitor Ku55933 (10 μM) or Ku60019 (2 μM) (Calbiochem, currently Merck Millipore) was used to inhibit ATM activity in wild type neurons. shRNA against Atm was used to study the effect of gene knockdown. shRNA against mouse ATM [pGFP-C-shLenti-ATM (TL500154), OriGene] were transfected with Lipofectamine LTX (Life Technologies). Six hours after transfection, cells were refreshed with culture medium and further incubated for 48 h for gene knockdown prior to being challenged at different glutamine concentrations for another 72 h.
Western blots and immunocytochemistry
For western blot analysis, cultured neurons were lysed in RIPA buffer (Thermo Scientific) containing proteinase and phosphatase inhibitors (Roche Diagnostics). Equal amounts of protein were separated on 4–20 % SDS PAGE gradient gels (Bio-Rad) and then transferred to PVDF or nitrocellulose membranes (Bio-Rad) for immunodetection. Primary antibodies used were: ATM2c1 and 53BP1 (Abcam); Actin (Santa Cruz Biotechnology); GFAP, GS, mTOR and P-mTORs2448 (Cell Signaling); and tau3R (Millipore). Secondary antibodies were chicken anti-rabbit IgG-HRP and chicken anti-mouse IgG-HRP (Santa Cruz Biotechnology). Chemiluminescent substrates used were SuperSignal™ West Pico Chemiluminescent Substrate and SuperSignal™ West Femto Maximum Sensitivity Substrate (Thermo Scientific). For immunofluorescence staining, neurons were fixed in 4 % paraformaldehyde for 30 min. Fixed cells were then incubated in blocking buffer (10 % goat serum, 0.5 % Triton X100 in PBS) for 1 h. Primary antibody HDAC4 (1:1000, Abcam) incubation were carried out in 4°, overnight. Alexa linked secondary antibodies (Life Technologies) were used to detect the presence of the HDAC4 antigens. Stained cells were photographed and viewed at a final magnification of 200 using Leica Application Suite/Leica DM5000B.
RT PCR and real-time PCR
For 36B4 (control)
For mBDNF (common region)
Field potential recording
Extracellular recordings of field EPSPs (fEPSPs) were made with ACSF-filled glass electrodes (5–10 μm tip diameter) according to protocols previously established in our lab . For baseline recordings, test stimuli (0.1 ms) were delivered with a bipolar platinum/iridium stimulating electrode at 1 min intervals. For recordings of CA1 activation by Schaffer collateral stimulation, recording and stimulating electrodes were both placed in stratum radiatum. Each experiment was begun by obtaining input–output relationships to establish the strength of baseline synaptic transmission. A Grass S8800 stimulator connected to a Grass PSIU6 photoelectric stimulus isolation unit was used to deliver a series of increasing intensity constant current pulses. Current magnitude is adjusted to elicit responses ranging from just-suprathreshold to near maximal. Following this, stimulus intensity was adjusted to evoke fEPSPs 30–40 % of maximum, typically 30–40 μA. To elicit long-term potentiation (LTP), theta burst stimulation (TBS) was used. A single stimulus consists of 6–12 bursts of four 100 Hz pulses spaced 200 ms apart. Response magnitude was quantified using the slope of the field potential.
Human A-T and mouse Atm −/− gene expression datasets were published previously  and are available from the NIH GEO archive under accession numbers GSE50951 and GSE61019.
For lifespan study, the significance of the difference between the glutamine and control curves was determined by the Mantel-Cox log-rank test. For the rest of the studies, the p values were determined by Student t-test. *** denotes p < 0.001; ** denotes p < 0.01; * denotes p < 0.05; n.s. means p ≥ 0.05.
Glutamine modulates the metabolomics of ATM deficiency
Glutamine supplementation modulates synaptic plasticity
Glutamine prolongs the lifespan of the ATM−/− mice
Gene expression changes in glutamine metabolism in A-T brains
Having identified significant changes in individual gene expression, we then re-queried the entire database using Ingenuity Pathway Analysis software to help identify ensembles of genes whose expression was significantly changed in A-T brains (≥1.5 fold, p ≤ 0.05). Upstream Regulator Analysis (URA) identifies molecules upstream of the genes in the data set that potentially explain the observed expression changes . Based on the list of significantly down regulated genes, URA predicted glutamine to be a likely upstream regulator with an overlap p value of 0.001 (Fisher’s exact test) and an activation Z score of 0.03. This suggests that glutamine target genes are significantly enriched in the group of genes that are down regulated in A-T. One additional finding of this analysis that we found particularly reassuring given our earlier work [4, 5] was that NFkB and TNF were predicted to be the upstream regulators for the significantly up-regulated genes, as previous studies have documented constitutional activation of NFkB signaling in ATM-deficient cells [26, 27].
Glutamine-deprivation leads to reduced ATM expression and deregulation of the mTOR pathway
In cultured wild-type mouse neurons, low exogenous glutamine almost completely suppresses mTOR phosphorylation (Fig. 8b, compare lane 4 to lane 1), while inhibiting endogenous glutamine production increases it (compare lane 2 to lane 1). This increase is completely dependent on exogenous glutamine (compare lane 5 to lane 2), as well as ATM activity (compare lane 2 to lane 3). These observations confirm the relation between glutamine, ATM and mTOR. Of note is the fact that the basic cytoarchitecture of the cells, as measured by the concentrations of the microtubule associated protein tau, seems largely unaffected by either ATM or GS inhibition.
ATM-deficient neurons are more dependent on exogenous glutamine
ATM is required throughout the lifetime of a neuron. It is the primary mediator of the response to DNA double strand breaks that arise from exposure to ionizing radiation. However, cells lacking ATM are also hypersensitive to insults other than double strand breaks, particularly oxidative stress. Since glutamine is essential for these responses , we hypothesized that ATM-deficient cells in culture would be more dependent on exogenous glutamine.
Cultured neurons exposed to exogenous stressors such as DNA damage, heavy metals, oxidation or the Aβ peptide have heightened vulnerability to glutamine deprivation . In mouse models of familial Alzheimer’s disease (AD), oral glutamine supplementation reduces phosphorylated tau as well as the ectopic appearance of neuronal cell cycle proteins . We have now extended these AD-related studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). The AD model we tested was the R1.40 mouse . These animals are a faithful genetic mimic of early-onset APP-driven dominantly inherited forms of human familial AD. Ataxia-telangiectasia is a recessive genetic condition of childhood neurodegenerative disease caused by mutations in the ATM gene. It is a true multi-systemic disease, but the neurological symptoms are the most prevalent and the most debilitating. On the surface, AD and A-T seem like very differences diseases, but our research shows that glutamine has a positive impact on the phenotype of both. This may be mediated through ATM, as we have recently discovered that AD patients often exhibit ATM deficiency, as seen through HDAC4 nuclear translocation in hippocampal neurons . Our finding on the powerful neuroprotective effects of glutamine in mouse models in both AD and A-T suggests that its benefits are not disease specific, and may be extrapolated to other neurodegenerative disorders – even beyond AD and A-T. Indeed, Rozas et al.  have recently shown that glutamine supplementation prolongs the survival of mice with tuberous sclerosis, an autosomal dominant neurodevelopmental disease.
Our discovery that glutamine and ATM interact to influence blood glucose, body weight and the phosphorylation of mTOR emphasizes that, beyond the DNA damage response, ATM has deep connections with the fundamental pathways of cellular metabolism. This largely cytoplasmic function of ATM is increasingly recognized [30, 37–39] and applies to energy metabolism in mitochondria as well. Indeed, A-T patients have an unusual form of diabetes , and present with irregularities in their glucose utilization . A recent study also revealed that adult asymptomatic relatives of A-T patients (who would be expected to carry a single mutated allele of ATM) have decreased glucose metabolism in cerebellar vermis and hippocampus . Additionally, we note that loss of retinoblastoma (pRB) results in reduced glucose utilization and enhanced susceptibility to oxidative stress. Glutamine rescues these effects by providing an alternative to glucose oxidation and enhancing glutathione production . The suggestion is that the effects of glutamine on ATM-deficient neurons that we report may share similarities with RB-deficient cells. The findings by Rozas et. al., showing that glutamine supplementation could prolong survival of mice with tuberous sclerosis, take on added significance in this context. Tsc2 knockout mice supplemented with glutamine survive 2 weeks longer than those without glutamine supplement, a 20 % increase in lifespan . TSC2 is a potent mTOR suppressor and it is noteworthy that ATM activates TSC2 to repress mTOR complex1 in response to oxidative stress . These observations support our suggestion that glutamine may exert its protective effect on Atm −/− mice by modulating mTOR activity. It is likely that part of this pathway passes through an ATM node, but the finding of Rozas suggest that passage through a TSC2 node is also possible.
Glutamine is not itself a neurotransmitter but it serves as an immediate precursor for glutamate and is only two steps removed from GABA. It has been shown that presynaptic glutamine transport is involved in the maintenance of excitatory synaptic currents , and glutamine supplementation rescues the rapid synaptic GABA depletion induced by astrogliosis, thus restoring inhibitory synaptic currents in mouse CA1 neurons . Given that ATM is involved in neuronal vesicle trafficking  and its concentrations are sensitive to the availability of glutamine (Fig. 8 and reference ) it is tempting to speculate that glutamine increases the small amounts of residual ATM protein found in the Atm −/− brain  thus partially restoring function.
Several additional features of the LTP experiments deserve mention. First, because our measurements were made in isolated brain slices over a period of several hours, it would appear that the effects of glutamine are long-term in nature rather than reflecting short-term, moment-to-moment, changes in transmitters. The recording medium, in which the slices were bathed during our measurements, contained only balanced salt solution and no added glutamine. Therefore, the LTP differences must represent chronic changes that remain stable even after the extracellular environment of the synapse is changed. Second, RT-PCR results revealed a partial rescue of BDNF mRNA (common exon) and almost total restoration of exon 4 expression after glutamine supplementation (8 mM) in KU-treated neurons (Fig. 11). This, combined with the fact that glutamine’s effects on LTP are strongest in late-LTP, which is dependent on BDNF , makes it possible that glutamine acts through restoration of BDNF in the same way that it improves stress-response proteins such as 53BP1, ATM, ATR, etc.
Untreated Atm −/− mice present with lower blood glutamine concentrations suggesting that glutamine metabolism may be impaired in A-T patients as well. The expression data summarized in Fig. 7 are consistent with this conclusion, and the independent URA analysis further supports the importance of glutamine in the changes in homeostasis brought on by ATM deficiency. Examination of the pathways involved suggests that while glutamine conversion to glutamate is likely upregulated in A-T, the pathways leading beyond glutamate are reduced (at least in brain). This would be predicted to deplete local glutamine stores, possibly at the expense of side pathways leading to asparagine and glucosamine (Fig. 7). This decrease in side pathway products could have a multitude of negative effects. For example, decreased asparagine would be expected to be destructive. ASNS-deficiency leads to progressive cerebral atrophy and intellectual disability  and can cause severe neurological impairment without involvement of peripheral tissues. Because of the poor transport of asparagine across the blood–brain barrier, the brain depends on local synthesis, suggesting that even a small block in its synthesis could have huge effects on brain function . Glutamine is also an important precursor for de novo synthesis of arginine in humans . Recent studies suggest that low level of total brain arginine contribute to neurodegeneration in Alzheimer’s disease ; a similar pathway may work in A-T brains too. Decreased GFPT expression predicts a lower glucosamine production in A-T brains. Glucosamine exerts a neuroprotective effect via suppression of inflammation through its ability to inhibit NFkB activation ; therefore, lower glucosamine would forecast higher NFkB activity in A-T brains. Other changes predicted from the expression array data enhance the picture further. For example, α-ketoglutarate is a major metabolite that feeds directly into TCA cycle and its reduction would result in lower cellular energy. Reduced GAD can lead to reduced GABA synthesis and decreased GABAergic transmission. Lastly, since GSS catalyzes the final step of glutathione production and its expression was significantly reduced in A-T, a situation of lower glutathione production with concomitant reduction in anti-oxidant defenses would be predicted.
Glutamine is known to support fast growing cells in culture and in tumor grafts . Indeed tumor cells are often described as ‘addicted’ to glutamine . An oft-cited reason for the low life expectancy of Atm −/− mice (about 3 months in our colony) is their high cancer predilection. Almost all Atm −/− mice die of thymic lymphomas. Thus we initially worried that, despite its significant neuroprotective properties, by elevating systemic concentrations of glutamine to improve nervous function we would be promoting the establishment and growth of tumors in the Atm −/− mice. Rather than causing premature death, however, oral glutamine supplementation paradoxically increased the lifespan of the Atm −/− mice by about one-third. In fact, Atm −/− mice supplemented with glutamine appeared to have slower tumor progression (Fig. 6). In line with our observations in Atm −/− mice, it has been shown that rats with carcinoma had significantly lower muscle glutamine content and the size of tumor negatively correlated with the glutamine level . Significantly lower plasma glutamine level has also been reported in breast cancer patients and in male gastrointestinal cancer patients . The implication is that glutamine’s effect on tumor growth is context-dependent . Both human and animal studies suggest that glutamine can be given to breast cancer patients without stimulating tumor growth or metastasis. The reasons for this are unknown, but glutamine generally strengthens the immune system, especially the natural killer cells, and thus might boost the body’s own defenses against cancer [53–55]. Whatever the ultimate explanation, it would appear in the right clinical circumstances it is possible to take advantage of the ability of glutamine to improve brain function yet not hasten death due to cancer.
We have shown previously that glutamine is neuroprotective in vitro and in mouse models of AD. We have now extended these AD-related studies to A-T. Unlike AD, A-T is entirely a genetic disease, yet the epigenetic landscape of the chromatin is part of the realization of the phenotype. To the extent that the disease symptoms result in part from these epigenetic changes, it is reasonable to predict that environmental factors can alter the timing and perhaps the extent of various disease events. Our data suggest that glutamine is a powerful part of an organism’s internal environment, and that changes in its concentrations have a huge impact on the function of the organism in general and the brain in particular. Glutamine supplementation is a promising therapeutic candidate for the treatment of human AD, A-T and beyond.
53BP1, p53-binding protein 1; AD, Alzheimer’s disease; A-T, ataxia telangiectasia; ATM, ataxia telangiectasia mutated; BDNF, brain-derived neurotrophic factor; CA1, cornus ammonis 1, region 1 of hippocampus proper; fEPSPs, extracellular recordings of field excitatory postsynaptic potential; GABA, γ-aminobutyric acid; GAD, glutamate decarboxylase; GEO, gene expression omnibus; Gln or Q, glutamine; GLS, glutaminase; GOT/GPT, glutamic oxaloacetic (pyruvate) transaminase; GSS, glutathione synthetase; HDAC4, histone deacetylase 4; IL8, interleukin 8; LTP, Long term potentiation; MSO, methionine sulfoximine; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; RT-PCR - reverse transcription polymerase chain reaction; shRNA - short hairpin RNA; TBS, theta burst stimulation; TCA, tricarboxylic acid cycle; TSC2, Tuberous Sclerosis Complex 2
The authors thank Dr. Ping Xie for her help with plotting survival cure and statistics, Ms Li Deng and Dr. Jay Tischfield for their support with real-time PCR.
This work is supported by grants from the BrightFocus Foundation A2012101, from NIH 1R01NS071022 and from the Hong Kong Research Grants Council HKSAR (GRF660813).
Availability of supporting data and materials
All data generated or analyzed during this study are included in this published article.
JC and KH designed the study. YC, JC, LL carried out the blood glutamine, glucose, body weight and life span studies and involved in the data analysis. JC, YC, HC and YZ did the neuronal culture experiments (RT-PCR, western blot and immunostaining) and participated in data analysis. GV and MP carried out LTP recording experiments and data analysis. JL and RH performed the expression studies and data analysis. JC drafted the manuscript. JC, KH, HC, RH and MP participated in the revision of the manuscript. All authors read and approved the manuscript.
The authors declare that they have no competing interest.
Consent for publication
Ethical approval and consent to participate
All animal procedures were approved by the Rutgers University Institutional Animal Care and Use Committee (protocol# 06–027).
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