Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington's disease mice.
Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington's disease mice.
复制标题
DOI：
10.1186/s40478-014-0178-7
复制
发表时间：
2014-12-20
影响因子：
7.1
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
McClory H;Williams D;Sapp E;Gatune LW;Wang P;DiFiglia M;Li X
亨廷顿氏病（HD）通过尚不清楚的机制扰乱了大脑中的葡萄糖代谢。HD神经元有葡萄糖摄取缺陷，这种缺陷在增强rab11活性后减弱。Rab11调节许多受体和转运体到细胞表面；其在HD细胞中的活性降低影响转铁蛋白受体和神经元谷氨酸/半胱氨酸转运体EAAC1的再循环。葡萄糖转运蛋白3 （Glut3）处理神经元中大部分的葡萄糖摄取。在这里，我们研究了rab11参与Glut3的贩运。通过免疫荧光标记将Glut3定位于原代神经元和永活纹状体细胞的rab11阳性点，并通过Western blot在小鼠脑免疫分离的rab11富集核内体中检测到。在克隆纹状体细胞中，显性活性和阴性rab11突变体的表达改变了细胞表面Glut3的水平，表明rab11对其有调控作用。约4%的Glut3发生在原代WT神经元的细胞表面。HD140Q/140Q神经元的细胞表面Glut3明显少于WT神经元。Western blot分析显示，WT和HD140Q/140Q小鼠纹状体和皮层中Glut3水平相当。然而，用识别Glut3细胞外表位的抗体免疫标记的脑切片显示，与WT小鼠相比，HD140Q/140Q小鼠纹状体和皮层中Glut3的表面表达减少。不依赖于rab11的GABAα1受体的表面标记在WT和HD140Q/140Q小鼠脑切片之间没有差异。这些数据将Glut3定义为依赖于rab11的转运货物，并表明由rab11功能障碍引起的Glut3转运受损是HD中观察到的葡萄糖低代谢的基础。
Huntington’s disease (HD) disturbs glucose metabolism in the brain by poorly understood mechanisms. HD neurons have defective glucose uptake, which is attenuated upon enhancing rab11 activity. Rab11 regulates numerous receptors and transporters trafficking onto cell surfaces; its diminished activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1. Glucose transporter 3 (Glut3) handles most glucose uptake in neurons. Here we investigated rab11 involvement in Glut3 trafficking. Glut3 was localized to rab11 positive puncta in primary neurons and immortalized striatal cells by immunofluorescence labeling and detected in rab11-enriched endosomes immuno-isolated from mouse brain by Western blot. Expression of dominant active and negative rab11 mutants in clonal striatal cells altered the levels of cell surface Glut3 suggesting a regulation by rab11. About 4% of total Glut3 occurred at the cell surface of primary WT neurons. HD140Q/140Q neurons had significantly less cell surface Glut3 than did WT neurons. Western blot analysis revealed comparable levels of Glut3 in the striatum and cortex of WT and HD140Q/140Q mice. However, brain slices immunolabeled with an antibody recognizing an extracellular epitope to Glut3 showed reduced surface expression of Glut3 in the striatum and cortex of HD140Q/140Q mice compared to that of WT mice. Surface labeling of GABAα1 receptor, which is not dependent on rab11, was not different between WT and HD140Q/140Q mouse brain slices. These data define Glut3 to be a rab11-dependent trafficking cargo and suggest that impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD.
登录
查看更多内容
影响因子：
5.3
作者：
Li, Xueyi;Standley, Clive;DiFiglia, Marian
通讯作者：
DiFiglia, Marian
影响因子：
3.3
作者：
Choeiri, C;Staines, W;Messier, C
通讯作者：
Messier, C
DOI：
10.1152/ajpendo.00344.2006
发表时间：
2007-05-01
影响因子：
5.1
作者：
Ganguly, Amit;McKnight, Robert A.;Devaskar, Sherin U.
通讯作者：
Devaskar, Sherin U.
影响因子：
14.5
作者：
KUWERT, T;LANGE, HW;FEINENDEGEN, LE
通讯作者：
FEINENDEGEN, LE
影响因子：
9.9
作者：
MARTIN, WRW;CLARK, C;HAYDEN, MR
通讯作者：
HAYDEN, MR