Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model |
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Authors: | S. Sreenivasa Reddy Karnam ShruthiV. Sudhakar Reddy G. RaghuP. Suryanarayana N.V. GiridharanG. Bhanuprakash Reddy |
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Affiliation: | Biochemistry Division, National Institute of Nutrition, Hyderabad, India |
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Abstract: | BackgroundObesity is associated with various progressive age-related diseases, including neurological disorders. However, underlying molecular basis for increased risk of neurodegeneration in obesity is unknown. A suitable animal model would immensely help in understanding the obesity-linked neurological problems.MethodsA spontaneously developed obese rat (WNIN/Ob) which is highly vulnerable for a variety of degenerative diseases was isolated from the existing WNIN stock rats. Ultrastructure of neurons in the cerebral cortex of 12-month old obese rats was evaluated by transmission electron microscopy. qRT-PCR and immunoblotting of ubiquitin C-terminal hydrolases (UCHs), ubiquitin, proteasomal sub-units, markers of ER stress and apoptosis were performed in the cerebral cortex. Proteasome activity was assayed by fluorometric method. Immunohistochemistry was performed for mediators of apoptosis, which was further confirmed by TUNEL assay. These investigations were also carried in high-fat diet-induced obese rat model.ResultsNeurons in the cerebral cortex of 12-month obese rats showed swollen mitochondria, disrupted ER and degenerating axons, nucleus and finally neurons. Results showed altered UPS, existence of ER stress, up-regulation of apoptotic markers and apoptosis in the cerebral cortex of obese rats. It appears that UCHL-1 mediated apoptosis through stabilizing p53 might play a role in neuronal cell death in obese rat. Similar changes were observed in the brain of diet-induced obese WNIN rats.ConclusionAltered UPS could be one of the underlying mechanisms for the neuronal cell death in obese conditions.General significanceThis is the first report to highlight the role of altered UPS in neurodegeneration due to obesity. |
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Keywords: | DUB, deubiquitinase ER stress, endoplasmic reticulum stress TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling UCH, ubiquitin C-terminal hydrolase UPS, ubiquitin proteasome system UPR, unfolded protein response |
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