Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model

• Published in: Biochimica et biophysica acta Vol. 1840; no. 9; pp. 2924 - 2934
• Main Authors: Reddy, S. Sreenivasa, Shruthi, Karnam, Reddy, V. Sudhakar, Raghu, G., Suryanarayana, P., Giridharan, N.V., Reddy, G. Bhanuprakash
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2014
• Subjects: animal models; Animals; Apoptosis; axons; Brain; cerebral cortex; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Disease Models, Animal; Endoplasmic Reticulum Stress; fluorometry; immunoblotting; immunohistochemistry; mitochondria; Nerve Tissue Proteins - metabolism; neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; Obesity; Obesity - chemically induced; Obesity - metabolism; Obesity - pathology; Proteasome; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - metabolism; quantitative polymerase chain reaction; Rats; reverse transcriptase polymerase chain reaction; risk; transmission electron microscopy; Tumor Suppressor Protein p53 - metabolism; ubiquitin; Ubiquitin - metabolism; Ubiquitin C-terminal hydrolase; Ubiquitin Thiolesterase - metabolism; ultrastructure; DUB; Obesity; Brain; TUNEL; UPR; ER stress; UPS; UCH; Ubiquitin C-terminal hydrolase; Endoplasmic reticulum stress; Proteasome; Apoptosis
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.06.005

Obesity 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. A 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. Neurons 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. Altered UPS could be one of the underlying mechanisms for the neuronal cell death in obese conditions. This is the first report to highlight the role of altered UPS in neurodegeneration due to obesity. [Display omitted] •Various neurodegenerative diseases are associated with obesity.•Shown neuronal apoptosis in a spontaneous obese rat model, WNIN/Ob rat•Up-regulated UHL-1 could mediate apoptosis probably by stabilizing p53 in obese rat.•Declined proteasomal activity triggers ER stress.•Altered UPS appears to be associated with neuronal cell death in obese rat model.