title: Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Altered UPS could be one of the underlying mechanisms for the neuronal cell death in obese conditions.
  
  
  CONCLUSIONS
  This is the first report to highlight the role of altered UPS in neurodegeneration due to obesity.
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
authors.forename: S Sreenivasa
authors.initials: SS
authors.lastname: Reddy
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
authors.forename: Karnam
authors.initials: K
authors.lastname: Shruthi
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
authors.forename: V Sudhakar
authors.initials: VS
authors.lastname: Reddy
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
authors.forename: G
authors.initials: G
authors.lastname: Raghu
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
authors.forename: P
authors.initials: P
authors.lastname: Suryanarayana
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
authors.forename: N V
authors.initials: NV
authors.lastname: Giridharan
authors.affiliation: Biochemistry Division, National Institute of Nutrition, Hyderabad, India. Electronic address: geereddy@yahoo.com.
authors.forename: G Bhanuprakash
authors.initials: GB
authors.lastname: Reddy
mesh_terms: D000818:Animals; D017209:Apoptosis; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: Apoptosis; Brain; Endoplasmic reticulum stress; Obesity; Proteasome; Ubiquitin C-terminal hydrolase