Effect of Sex on Lifespan, Disease Progression, and the Response to Methionine Sulfoximine in the SOD1 G93A Mouse Model for ALS

Bame, Monica; Pentiak, Patricia; Needleman, Richard; Brusilow, William S.A.

doi:10.1016/j.genm.2012.10.014

Cited by 39 publications

(29 citation statements)

References 19 publications

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“…Riluzole, an inhibitor of glutamate release, is the only effective drug for ALS, and it prolongs survival by 3-6 mo (64). Administration of the GS inhibitor MSO to SOD1 G93A transgenic mice, which develop a phenotype similar to ALS in humans, decreases both glutamine and glutamate levels in the brain and significantly extends the lifespan of these mice (65,66). Therefore, it will be of ---- 2 1.1 0.5 1.2 1 1 0.6 1 1.1 1.2 1.1 1 0.4 1.1 0.9 1.2 1 1 1.1 1 1.1 1 0 (E) U937 and MM1S cells were pretreated (or not) with CB-5083 (2 or 10 μM), MLN4924 (1 μM), or MG132 (10 μM) for 1 h, followed by treatment with 10 nM CC-885 for an additional 2 h. Whole-cell extracts were subjected to immunoblot analysis.…”

Section: Discussionmentioning

confidence: 99%

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

Nguyen

Lu³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4 CRBN and p97 pathways.lutamine plays important roles in many cellular processes, including oxidative metabolism and ATP generation, biosynthesis of proteins, lipids, and nucleic acids, and cell growth and proliferation through the regulation of the mTOR signaling pathway, translation, and autophagy (1, 2). In mammals, it is the most abundant amino acid in plasma with a concentration of 0.5-0.9 mM (3), accounting for ∼20% of its free amino acid pool. Glutamine synthetase (GS) is the only enzyme that is capable of de novo synthesis of glutamine and also functions to detoxify glutamate and ammonia, depending on tissue localization. Skeletal muscles and lungs are major sites of glutamine synthesis, whereas cells of the gut and the immune system, such as lymphocytes and macrophages, consume large amounts of glutamine in plasma (4). GS protects neurons against excitotoxicity by converting glutamate into glutamine in brain, detoxifies ammonia in liver, and maintains physiologic pH in kidney (5). In an attempt to investigate the role of GS in development, He et al. generated GS-knockout mice and reported that GS is essential in early embryogenesis, because deletion of the murine GLUL gene causes lethality at the blastocyst stage (embryonic day 3.5) (6). Interestingly, mouse ES cells maintain pluripotency and proliferate when grown in the absence of exogenous glutamine (7). However, inhibition of GS with the small molecule methionine sulfoximine (MSO) is sufficient to block the proliferation of ES cells in glutamine-free medium (7). In humans, congenital systemic glutamine deficiency caused by homozygous GS mutations results in multiorgan failure and neonatal death (8).Recent studies highlight the importance of glutamine metabolism in metabolic reprogramming, because many tumor cells display "glutamine addiction" (9). Activation of oncogenes such as MYC, KRAS, and HIF1α and/or loss of tumor suppressor genes including p53 can directly mediate the reprogramming of glutamine metabolism by selectively activating their downstream signaling or metabolic pathway...

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Section: Discussionmentioning

confidence: 99%

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

Nguyen

Lu³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…An overproduction of glutamine in astrocytes is a contributing factor to the neurotoxicity associated with hyperammonemia [104] and may contribute to the production of excess excitatory glutamate in a mouse model of amyotrophic lateral sclerosis [100][101][102]. It is interesting that a potent inhibitor of glutamine synthetase, namely MSO, is neuroprotective in animal models of hyperammonemia [103,104] and in a mouse model of amyotrophic lateral sclerosis [100][101][102]. We hypothesize that cerebral ischemia-reperfusion injury may result, at least in part, from overproduction of glutamine, which in turn may result in increased levels of excitatory glutamate.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is possible that increased activity contributes to glutamate excitotoxicity by supplying glutamine to neurons for eventual release as glutamate. This idea was the basis for the use of a glutamine synthetase inhibitor-MSO-to treat the G93A superoxide dismutase 1 murine model of amyotrophic lateral sclerosis [100][101][102]. The administration of MSO decreased both the contents of glutamate and glutamine in the G93A superoxide dismutase 1 mice [102].…”

Section: Glutamine Synthetase and Strokementioning

confidence: 99%

Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke

2015

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The following article addresses some seemingly paradoxical observations concerning cerebral glutamine synthetase in ischemia-reperfusion injury. In the brain, this enzyme is predominantly found in astrocytes and catalyzes part of the glutamine-glutamate cycle. Glutamine synthetase is also thought to be especially sensitive to inactivation by the oxygen- and nitrogen-centered radicals generated during strokes. Despite this apparent sensitivity, glutamine synthetase specific activity is elevated in the affected tissues during reperfusion. Given the central role of the glutamine-glutamate cycle in the brain, we sought to resolve these conflicting observations with the view of providing an alternative perspective for therapeutic intervention in stroke.

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“…In a very recent study conducted on a rat model of ALS, it was determined that onset of the disease, progression, and survival were related to the gender; male rats lost weight earlier and died earlier [37]. In other studies conducted with transgenic rats, it was reported that gender was significant in terms of prognosis, with female gender having more positive prognostic characteristics and more positive responses to the treatment given [38,39]. One limitation of our study is that statistical analyses could not be performed for certain factors due to the small number of patients.…”

Section: Discussionmentioning

confidence: 99%

Clinical, demographic and prognostic features of sporadic amyotrophic lateral sclerosis in Northern Turkey

Aksoy

Çevik

Solmaz

et al. 2013

International Journal of Neuroscience

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which progression cannot be prevented. In this study, we evaluated 37 patients diagnosed with sporadic definitive-probable ALS who were monitored in our neurology clinic between 2002 and 2012 in terms of age, gender, profession, onset, and clinical course within the disease process. The hospital ethics committee approved the study. Nineteen female and 18 male patients diagnosed with sporadic definitive or probable ALS were evaluated for age, gender, level of education, residence, onset of disease, the time between the first symptom and diagnosis, and average lifetime after diagnosis. Twenty-eight of the patients had graduated from primary-secondary school, six were illiterate, and three of them were college graduates. Eighteen patients were living in city center, 19 were living in the country. Fourteen patients were farmers, 11 were housewives, and the remaining was working in various different occupations. The age of onset was 62.13. The men and women were diagnosed 10.27 months and 17.91 months after the first symptom, respectively (p = 0.001). The average survival time after diagnosis was 36.70 months for males and 49.80 months for females (p < 0.05). This difference was particularly evident among patients from rural areas. In addition, our female patients required interventions such as ventilation at a later period than did males. In conclusion, female gender seems to be one of the good prognostic factors for our ALS patients. This may be due to the protection by hormonal mechanisms in women or differences in their responses to exogenous toxins.

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Effect of Sex on Lifespan, Disease Progression, and the Response to Methionine Sulfoximine in the SOD1 G93A Mouse Model for ALS

Cited by 39 publications

References 19 publications

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke

Clinical, demographic and prognostic features of sporadic amyotrophic lateral sclerosis in Northern Turkey

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