Increased protein aggregation in Zucker diabetic fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide.
Increased protein aggregation in Zucker diabetic fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide.
复制标题
DOI：
10.1186/1471-2121-15-1
复制
发表时间：
2014-01-06
期刊：
影响因子：
--
通讯作者：
Henning RH
中科院分区：
文献类型：
--
作者：
Talaei F;Van Praag VM;Shishavan MH;Landheer SW;Buikema H;Henning RH
糖尿病和特别是高血糖水平与神经变性有关。神经变性的标志之一是蛋白质聚集。我们研究了糖尿病动物模型Zucker糖尿病脂肪（ZDF）大鼠额叶中蛋白质聚集的存在。此外，评估了NaHS在抑制来自ZDF的培养脑切片中的蛋白质聚集中的作用。在ZDF和对照（瘦）脑中评估蛋白质合成、蛋白质/基因表达、自噬和抗氧化防御的水平。与瘦相比，ZDF脑显示蛋白质聚集体、p-tau、纤连蛋白表达和蛋白质糖基化的显著增加。ZDF中mTOR和S6核糖体蛋白的磷酸化增加表明蛋白质合成增加，而ZDF脑中泛素化蛋白和LC 3-I的增加伴随着LC 3-II表达和LC 3-II/LC 3-I水平的降低表明蛋白水解途径的阻断。与瘦型相比，ZDF脑中的CBS（胱硫醚β合酶）蛋白和mRNA表达以及巯基水平较低。ZDF大脑显示出更高水平的活性氧。在体外NaHS治疗正常化蛋白质稳态，同时抵消氧化应激。我们的数据表明，增加蛋白质的合成和聚集在糖尿病ZDF大鼠脑，这是可逆的NaHS治疗。这是第一份关于NaHS作为一种新的抗糖尿病脑蛋白聚集策略的潜在用途的报告。
Diabetes and particularly high blood glucose levels are implicated in neurodegeneration. One of the hallmarks of neurodegeneration is protein aggregation. We investigated the presence of protein aggregation in the frontal brain of Zucker diabetic fatty (ZDF) rats, an animal model for diabetes. Further, the effect of NaHS in suppressing protein aggregation in cultured brain slices from ZDF was assessed. The levels of protein synthesis, protein/gene expression, autophagy and anti-oxidant defense were evaluated in ZDF and control (Lean) brains. Compared to Lean, ZDF brains displayed a significant increase in protein aggregates, p-tau, fibronectin expression and protein glycosylation. Increased phosphorylation of mTOR and S6 ribosomal protein in ZDF indicated higher protein synthesis, while the increase in ubiquitinated proteins and LC3-I in ZDF brains accompanied by lower LC3-II expression and LC3-II/LC3-I levels indicated the blockage of proteolytic pathways. CBS (cystathionine beta synthase) protein and mRNA expression and thiol group levels in ZDF brains were lower compared to Lean. ZDF brains show a higher level of reactive oxygen species. In vitro NaHS treatment normalized proteostasis while counteracting oxidative stress. Our data demonstrate increased protein synthesis and aggregation in the diabetic ZDF rat brain, which was reversible by NaHS treatment. This is the first report on the potential use of NaHS as a novel strategy against protein aggregation in diabetic brain.
登录
查看更多内容
影响因子：
4.8
作者：
Kimura, Y;Kimura, H
通讯作者：
Kimura, H
DOI：
10.1161/01.atv.0000258979.92828.bc
发表时间：
2007-04-01
影响因子：
8.7
作者：
Bonello, Steve;Zahringer, Christian;Goerlach, Agnes
通讯作者：
Goerlach, Agnes
影响因子：
13.6
作者：
Coughlan, Melinda T.;Thorburn, David R.;Forbes, Josephine M.
通讯作者：
Forbes, Josephine M.
影响因子：
3.6
作者：
Hu, Li-Fang;Lu, Ming;Bian, Jin-Song
通讯作者：
Bian, Jin-Song
影响因子：
2.7
作者：
Alvarez, Edgardo O.;Beauquis, Juan;Saravia, Flavia
通讯作者：
Saravia, Flavia