Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently described a homozygous frameshift mutation in the human leptin (ob) gene associated with undetectable serum leptin and extreme obesity in two individuals. This represented the first identified genetic cause of morbid obesity in humans. Preliminary data suggested a defect in the secretion of this truncated (delta133) mutant leptin. In the present investigation, we have examined the mechanisms underlying the defective secretion of the delta133 leptin in transient transfection studies in Chinese hamster ovary and monkey kidney epithelium cells. Consistent with our previous observations, only immunoreactive wild-type (wt) leptin was secreted. In pulse chase experiments, intracellular wt leptin levels decreased, concomitant with secretion into the medium. In contrast, though immunoreactive delta133 leptin disappeared from cell lysates with kinetics similar to those of wt leptin (half-life, 45 min), it was not detected in the medium. Inhibition of the proteasome, using the inhibitor clastolactacystin beta-lactone, led to a significant increase in the intracellular levels of delta133 leptin, indicating a role for the proteasome in the degradation pathway. Although intracellular immunoprecipitated wt and delta133 leptin levels were comparable, analysis of total cell lysates revealed a 7-fold increase in total intracellular delta133 leptin, compared with wt leptin. Size-exclusion membrane filtration demonstrated that intracellular delta133 leptin accumulated in an aggregated form, presumably as a result of misfolding in the endoplasmic reticulum. Consistent with this, an endoplasmic reticulum-like localization for delta133 leptin was detected by immunofluorescence microscopy. In conclusion, the delta133 mutant leptin is not secreted but accumulates intracellularly, as a consequence of misfolding/aggregation, and is subsequently degraded by the proteasome. These studies further define the genotype/phenotype correlation in this paradigmatic case of human leptin deficiency.
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PMID:Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport. 1009 8

Obesity is a health problem caused by a diet rich in energy and the sedentary lifestyle of modern societies. A leptin deficiency is one of the worst causes of obesity, since it results in morbid obesity, a chronic disease without a cure. Leptin is an adipokine secreted in a manner dependent on the circadian rhythm that ultimately reduces food intake. We studied cellular alterations in brain of leptin-deficient obese animals and tested whether these alterations are reflected in abnormal behaviors. Obesity induced increases in oxidative stress and the unfolded protein response caused by endoplasmic reticulum stress. However, the subsequent signaling cascade was disrupted, blocking possible systemic improvements and increasing the production of misfolded proteins that trigger autophagy. Up-regulated autophagy was not indefinitely maintained and misfolded proteins accumulated in obese animals, which led to aggresome formation. Finally, neurodegenerative markers together with anxiety and stress-induced behaviors were observed in leptin-deficient mice. As oxidative stress has an essential role in the development of these harmful effects of obesity, melatonin, a powerful antioxidant, might counteract these effects on the brain. Following treatment with melatonin, the animals' antioxidant defenses were improved and misfolded protein, proteasome activity, and autophagy decreased. Aggresome formation was reduced due to the reduction in the levels of misfolded proteins and the reduction in tubulin expression, a key element in aggresome development. The levels of neurodegenerative markers were reduced and the behaviors recovered. The data support the use of melatonin in therapeutic interventions to reduce brain damage induced by leptin deficiency-dependent obesity.
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PMID:Melatonin Prevents the Harmful Effects of Obesity on the Brain, Including at the Behavioral Level. 2908 46