Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model.
Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model.
复制标题
DOI：
10.1016/j.nbd.2013.06.002
复制
发表时间：
2013-10
影响因子：
6.1
通讯作者：
Gray M
中科院分区：
文献类型：
--
作者：
Lee W;Reyes RC;Gottipati MK;Lewis K;Lesort M;Parpura V;Gray M
尽管亨廷顿蛋白广泛表达于各种神经细胞类型，包括星形胶质细胞，但亨廷顿病(HD)会导致大脑中的一部分神经元优先丧失。谷氨酸介导的兴奋性毒性被认为导致选择性神经元损伤，而脑星形胶质细胞在调节细胞外谷氨酸方面起着核心作用。为了确定全长突变体Huntingtin的表达是否导致细胞自主表型和干扰星形胶质细胞神经胶质递质的释放，我们研究了来自BACHD小鼠的培养的皮质星形胶质细胞。在这里，我们报告了BACHD星形胶质细胞通过钙依赖的胞吐增加谷氨酸的释放。尽管这种释放通常依赖于细胞内的钙离子水平，但令人惊讶的是，我们发现BACHD星形胶质细胞表现出与野生型星形胶质细胞相当的钙动力学。这些结果表明，其他因素可能参与了调节星形胶质细胞谷氨酸的钙依赖/囊泡释放。我们发现了导致BACHD星形胶质细胞胞浆谷氨酸利用率增加的生化足迹：i)由于星形胶质细胞特有的线粒体酶丙酮酸羧基酶水平的增加而增加从头合成谷氨酸；以及ii)谷氨酸到谷氨酰胺的转化没有改变，因为星形胶质细胞特有的酶谷氨酰胺合成酶的表达水平没有变化。这项工作在星形胶质细胞中发现了一种新的机制，可能导致HD患者细胞外谷氨酸水平增加，从而可能导致这种毁灭性疾病的兴奋性毒性。
Huntington’s disease (HD) causes preferential loss of a subset of neurons in the brain although the huntingtin protein is expressed broadly in various neural cell types, including astrocytes. Glutamate-mediated excitotoxicity is thought to cause selective neuronal injury, and brain astrocytes have a central role in regulating extracellular glutamate. To determine whether full-length mutant huntingtin expression causes a cell-autonomous phenotype and perturbs astrocyte gliotransmitter release, we studied cultured cortical astrocytes from BACHD mice. Here, we report augmented glutamate release through Ca2+-dependent exocytosis from BACHD astrocytes. Although such release is usually dependent on cytosolic Ca2+ levels, surprisingly, we found that BACHD astrocytes displayed Ca2+ dynamics comparable to those in wild type astrocytes. These results point to a possible involvement of other factors in regulating Ca2+- dependent/vesicular release of glutamate from astrocytes. We found a biochemical footprint that would lead to increased availability of cytosolic glutamate in BACHD astrocytes: i) augmented de novo glutamate synthesis due to an increase in the level of the astrocyte specific mitochondrial enzyme pyruvate carboxylase; and ii) unaltered conversion of glutamate to glutamine, as there were no changes in the expression level of the astrocyte specific enzyme glutamine synthetase. This work identifies a new mechanism in astrocytes that could lead to increased levels of extracellular glutamate in HD and thus may contribute to excitotoxicity in this devastating disease.
登录
查看更多内容
影响因子：
11.2
作者：
ALBIN, RL;REINER, A;YOUNG, AB
通讯作者：
YOUNG, AB
影响因子：
14.5
作者：
Behrens, P. F.;Franz, P.;Landwehrmeyer, G. B.
通讯作者：
Landwehrmeyer, G. B.
影响因子：
9.9
作者：
Jenkins, BG;Rosas, HD;Koroshetz, WJ
通讯作者：
Koroshetz, WJ
影响因子：
16.2
作者：
Gu, XF;Li, CJ;Yang, XW
通讯作者：
Yang, XW
影响因子：
10.8
作者：
Gottipati, Manoj K.;Kalinina, Irina;Parpura, Vladimir
通讯作者：
Parpura, Vladimir