Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease
Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease
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DOI：
10.1016/j.nbd.2010.05.027
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发表时间：
2010-10-01
影响因子：
6.1
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Huang, Kun;Kang, Martin H.;Hayden, Michael R.
兴奋毒性在亨廷顿病（HD）纹状体神经元的选择性易损性中起关键作用。神经胶质细胞对谷氨酸摄取的减少可以解释HD患者和动物模型中突触处过量的谷氨酸。负责在突触处清除谷氨酸的主要分子是神经胶质谷氨酸转运体GLT-1。在这项研究中，我们表明，GLT-1是棕榈酰化的半胱氨酸38（C38），并进一步，这种棕榈酰化显着减少在HD模型在体外和体内。棕榈酰化是正常GLT-1功能所必需的。用一般棕榈酰化抑制剂2-溴棕榈酸酯或用GLT-1 C38 S突变阻断棕榈酰化严重损害谷氨酸摄取活性。此外，GLT-1介导的谷氨酸摄取在VAC 128 HD小鼠脑中确实受损，早在明显的神经病理学发现之前3个月，纹状体中的缺陷就很明显，并且在12个月时纹状体和皮质中都有缺陷。这些表型不是GLT 1蛋白表达变化的结果，表明棕榈酰化在GLT-1功能中起着至关重要的作用。因此，似乎受损的GLT-1棕榈酰化存在于HD发病机制的早期，并可能影响HD中谷氨酸摄取减少、兴奋性毒性和最终神经元细胞死亡。(C)2010年爱思唯尔公司All rights reserved.
Excitotoxicity plays a key role in the selective vulnerability of striatal neurons in Huntington disease (HD). Decreased glutamate uptake by glial cells could account for the excess glutamate at the synapse in patients as well as animal models of HD. The major molecule responsible for clearing glutamate at the synapses is glial glutamate transporter GLT-1. In this study, we show that GLT-1 is palmitoylated at cysteine38 (C38) and further, that this palmitoylation is drastically reduced in HD models both in vitro and in vivo. Palmitoylation is required for normal GLT-1 function. Blocking palmitoylation either with the general palmitoylation inhibitor, 2-bromopalmitate, or with a GLT-1 C38S mutation, severely impairs glutamate uptake activity. In addition, GLT-1-mediated glutamate uptake is indeed impaired in the VAC128 HD mouse brain, with the defect in the striatum evident as early as 3 months prior to obvious neuropathological findings, and in both striatum and cortex at 12 months. These phenotypes are not a result of changes in GLT1 protein expression, suggesting a crucial role of palmitoylation in GLT-1 function. Thus, it appears that impaired GLT-1 palmitoylation is present early in the pathogenesis of HD, and may influence decreased glutamate uptake, excitotoxicity, and ultimately, neuronal cell death in HD. (C) 2010 Elsevier Inc. All rights reserved.