Reddy S Sreenivasa, Shruthi Karnam, Reddy V Sudhakar, Raghu G, Suryanarayana P, Giridharan N V, Reddy G Bhanuprakash
Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
Biochim Biophys Acta. 2014 Sep;1840(9):2924-34. doi: 10.1016/j.bbagen.2014.06.005. Epub 2014 Jun 17.
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.
肥胖与多种与年龄相关的渐进性疾病有关，包括神经紊乱。然而，肥胖中神经退行性变风险增加的潜在分子基础尚不清楚。合适的动物模型将极大地有助于理解与肥胖相关的神经问题。
从现有的WNIN种群大鼠中分离出一种自发形成的肥胖大鼠（WNIN/Ob），其对多种退行性疾病高度易感。通过透射电子显微镜评估12月龄肥胖大鼠大脑皮质神经元的超微结构。在大脑皮质中进行泛素C末端水解酶（UCHs）、泛素、蛋白酶体亚基、内质网应激标志物和凋亡标志物的qRT-PCR和免疫印迹分析。通过荧光法测定蛋白酶体活性。对凋亡介质进行免疫组织化学分析，并通过TUNEL试验进一步证实。这些研究也在高脂饮食诱导的肥胖大鼠模型中进行。
12月龄肥胖大鼠大脑皮质中的神经元显示线粒体肿胀、内质网破坏以及轴突、细胞核最终神经元发生退化。结果显示肥胖大鼠大脑皮质中泛素蛋白酶体系统（UPS）改变、存在内质网应激、凋亡标志物上调以及凋亡。似乎UCHL-1通过稳定p53介导的凋亡可能在肥胖大鼠的神经元细胞死亡中起作用。在饮食诱导的肥胖WNIN大鼠的大脑中也观察到了类似的变化。
UPS改变可能是肥胖条件下神经元细胞死亡的潜在机制之一。
这是第一份强调UPS改变在肥胖所致神经退行性变中的作用的报告。
