Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamine synthetase (GS) is a key enzyme in the "glutamine-glutamate cycle" between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS(fl/lacZ) or GS(fl/fl) mice with hGFAP-Cre mice resulted in prenatal excision of the GS(fl) allele in astrocytes. "GS-KO/A" mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14-fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6-fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS-KO/A mice. The temporal dissociation between GS(fl) elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS-deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine-glutamate and the associated alanine-lactate cycles.
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PMID:Glutamine synthetase deficiency in murine astrocytes results in neonatal death. 2014 Sep 59

During autophagy, phagophores capture portions of cytoplasm and form double-membrane autophagosomes to deliver cargo for lysosomal degradation. How autophagosomes gain competence to fuse with late endosomes and lysosomes is not known. In this paper, we show that Syntaxin17 is recruited to the outer membrane of autophagosomes to mediate fusion through its interactions with ubisnap (SNAP-29) and VAMP7 in Drosophila melanogaster. Loss of these genes results in accumulation of autophagosomes and a block of autolysosomal degradation during basal, starvation-induced, and developmental autophagy. Viable Syntaxin17 mutant adults show large-scale accumulation of autophagosomes in neurons, severe locomotion defects, and premature death. These mutant phenotypes cannot be rescued by neuron-specific inhibition of caspases, suggesting that caspase activation and cell death do not play a major role in brain dysfunction. Our findings reveal the molecular mechanism underlying autophagosomal fusion events and show that lysosomal degradation and recycling of sequestered autophagosome content is crucial to maintain proper functioning of the nervous system.
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PMID:Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. 2381 62

Neurexins are neuronal adhesion molecules important for synapse maturation, function, and plasticity. Neurexins have been genetically associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia, but can have variable penetrance and phenotypic severity. Heritability studies indicate that a significant percentage of risk for ASD and schizophrenia includes environmental factors, highlighting a poorly understood interplay between genetic and environmental factors. The singular Caenorhabditis elegans ortholog of human neurexins, nrx-1, controls experience-dependent morphologic remodeling of a GABAergic neuron in adult males. Here, I show remodeling of this neuron's morphology in response to each of three environmental stressors (nutritional, heat, or genotoxic stress) when applied specifically during sexual maturation. Increased outgrowth of axon-like neurites following adolescent stress is the result of an altered morphologic plasticity in adulthood. Despite remodeling being induced by each of the three stressors, only nutritional stress affects downstream behavior and is dependent on neurexin/nrx-1 Heat or genotoxic stress in adolescence does not alter behavior despite inducing GABAergic neuron remodeling, in a neurexin/nrx-1 independent fashion. Starvation-induced remodeling is also dependent on neuroligin/nlg-1, the canonical binding partner for neurexin/nrx-1, and the transcription factors FOXO/daf-16 and HSF1/hsf-1 hsf-1 and daf-16, in addition, each have unique roles in remodeling induced by heat and UV stress. The differential molecular mechanisms underlying GABAergic neuron remodeling in response to different stressors, and the disparate effects of stressors on downstream behavior, are a paradigm for understanding how genetics, environmental exposures, and plasticity may contribute to brain dysfunction in ASDs and schizophrenia.
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PMID:Stress-Induced Neuron Remodeling Reveals Differential Interplay Between Neurexin and Environmental Factors in Caenorhabditis elegans. 3155 83

Anorexia nervosa is a chronic disorder of children, adolescents and young people typically characterised by self-starvation and resistance to interventions. Staff dealing with these young people frequently question patient motivations and the ethics of interventions that may be applied against the wishes of patients. The question of withdrawal of care in a subgroup of these patients has been raised. Futility is not an appropriate response to adolescent anorexia nervosa, and treatment withdrawal is not appropriate for a disorder in which most patients can be expected to recover, in which opposition to treatment is a characteristic of the disorder and in which brain dysfunction is precipitated by severe malnutrition.
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PMID:Futility in adolescent anorexia nervosa and the question of withdrawal of care. 3230 83