A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington's disease in mice.
A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington's disease in mice.
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DOI：
10.1038/ncomms3917
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发表时间：
2013
影响因子：
16.6
通讯作者：
Castro, Maite A.
中科院分区：
文献类型：
--
作者：
Acuna, Anibal I.;Esparza, Magdalena;Kramm, Carlos;Beltran, Felipe A.;Parra, Alejandra V.;Cepeda, Carlos;Toro, Carlos A.;Vidal, Rene L.;Hetz, Claudio;Concha, Ilona I.;Brauchi, Sebastian;Levine, Michael S.;Castro, Maite A.
亨廷顿氏病与能量代谢失败和氧化损伤有关。抗坏血酸是一种强大的抗氧化剂，高度集中在大脑中，它作为信使，调节神经元代谢。通过R6/2 HD切片的电生理方法，我们观察到星形胶质细胞到神经元的抗坏血酸通量异常，这是神经元代谢底物偏好改变的原因。在这里，我们使用来自表达突变亨廷顿蛋白的敲入小鼠（STHdhQ细胞）的纹状体神经元，研究抗坏血酸的转运。当细胞外抗坏血酸浓度增加时，如在突触活动期间发生的，抗坏血酸转运蛋白2 （SVCT2）易位到质膜，确保神经元最佳的抗坏血酸摄取。相反，来自模拟HD症状的细胞（称为HD细胞）的SVCT2在相同条件下无法到达质膜。我们推断，HD神经元抗坏血酸摄取的早期损伤可能导致早期代谢衰竭，促进神经元死亡。抗坏血酸通量缺陷是与亨廷顿氏病相关的代谢衰竭的标志。在这里，Acuña等人表明，星形胶质细胞的抗坏血酸通量减少先于小鼠亨廷顿病的症状，并损害神经元的抗坏血酸摄取。
Huntington’s disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death. Defective ascorbic acid flux is a sign of metabolic failure associated with Huntington’s disease. Here, Acuña et al. show that reduction in ascorbic acid flux from astrocytes precedes the symptoms of Huntington’s disease in mice and impairs ascorbic acid uptake in neurons.
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影响因子：
2.9
作者：
Dorner JL;Miller BR;Klein EL;Murphy-Nakhnikian A;Andrews RL;Barton SJ;Rebec GV
通讯作者：
Rebec GV
影响因子：
3.3
作者：
BOUTELLE, MG;SVENSSON, L;FILLENZ, M
通讯作者：
FILLENZ, M
影响因子：
5.6
作者：
Angulo, Constanza;Castro, Maite A.;Concha, Ilona I.
通讯作者：
Concha, Ilona I.
影响因子：
4.5
作者：
Castro, Maite A.;Angulo, Constanza;Concha, Ilona I.
通讯作者：
Concha, Ilona I.
影响因子：
2.9
作者：
BASSETOMUSK, A;REBEC, GV
通讯作者：
REBEC, GV