INHIBITION OF APOPTOSIS SIGNAL-REGULATING KINASE 1 REDUCES ENDOPLASMIC RETICULUM STRESS AND NUCLEAR HUNTINGTIN FRAGMENTS IN A MOUSE MODEL OF HUNTINGTON DISEASE
INHIBITION OF APOPTOSIS SIGNAL-REGULATING KINASE 1 REDUCES ENDOPLASMIC RETICULUM STRESS AND NUCLEAR HUNTINGTIN FRAGMENTS IN A MOUSE MODEL OF HUNTINGTON DISEASE
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DOI：
10.1016/j.neuroscience.2009.07.048
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发表时间：
2009-11-10
期刊：
影响因子：
3.3
通讯作者：
Kim, G. W.
中科院分区：
文献类型：
--
作者：
Cho, K. J.;Lee, B. I.;Kim, G. W.
亨廷顿病（HD）的临床特征是舞蹈病、精神障碍和痴呆，而其病理特征是神经元包涵体以及纹状体和皮质神经变性。神经变性是由于皮层和纹状体中长投射神经元的丧失引起的。在本研究中，我们研究了凋亡信号调节激酶 1 (Ask1) 在 HD 发病机制中的作用。我们分析了纹状体和皮质内 Ask1 和亨廷顿蛋白 (htt) 的表达，并检查了 HD (R6/2) 小鼠中 Ask1 与 htt 片段的相互作用。此外，我们抑制了 Ask1 并分析了脑源性神经营养因子 (BDNF) 表达、运动功能和纹状体萎缩的变化。使用针对 Ask1 蛋白 C 末端产生的 Ask1 抗体来阻断 Ask1 活性。使用微渗透泵将抗Ask1抗体注入HD小鼠的纹状体4周。 HD 小鼠的 Ask1 蛋白和内质网 (ER) 应激水平升高。失活的 Ask1 与 htt 片段的结合在细胞质中比在皮质神经元的细胞核中更普遍。失活的 Ask1 与 htt 片段的结合阻止了 htt 片段易位到细胞核中，从而改善了运动功能障碍和萎缩。在正常状态下，活跃的Ask1可能有助于htt片段进入细胞核，而失活的Ask1通过结合但不将片段化的htt释放到细胞核中来阻碍这种易位。我们认为 Ask1 可能与 htt 片段相互作用并随后诱导 ER 应激。 BDNF 耗竭可以通过针对 Ask1 来预防；这将减少内质网压力，并可能改善伴随 HD 的行为或解剖异常。因此，调节Ask1蛋白的数量和活性是治疗HD的新策略。 (C) 2009 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Huntington's disease (HD) is characterized clinically by chorea, psychiatric disturbances, and dementia, while it is characterized pathologically by neuronal inclusions as well as striatal and cortical neurodegeneration. The neurodegeneration arises from the loss of long projection neurons in the cortex and striatum. In this study, we investigated the role of apoptosis signal-regulating kinase 1 (Ask1) in the pathogenesis of HD. We analyzed the expression of Ask1 and huntingtin (htt) within the striatum and cortex and also examined the interaction of Ask1 with htt fragments in HD (R6/2) mice. Additionally, we inhibited Ask1 and analyzed the resulting changes in brain-derived neurotrophic factor (BDNF) expression, motor function, and striatal atrophy. Ask1 activity was blocked using an Ask1 antibody raised against the C-terminus of the Ask1 protein. The anti-Ask1 antibody was infused into the striatum of the HD mice for four weeks using a micro-osmotic pump. The levels of Ask1 protein and endoplasmic reticulum (ER) stress were increased in HD mice. Binding of inactivated Ask1 to htt fragments was more prevalent in the cytosol than the nucleus of cortical neurons. Binding of inactivated Ask1 to htt fragments prevented translocation of the htt fragments into the nucleus, resulting in an improvement in motor dysfunction and atrophy. In the normal state, active Ask1 may help htt fragments enter the nucleus, while inactivated Ask1 hinders this translocation by binding to but not releasing fragmented htt into the nucleus. We propose that Ask1 may interact with htt fragments and subsequently induce ER stress. BDNF depletion may be prevented by targeting Ask1; this would decrease ER stress and possibly ameliorate behavioral or anatomical abnormalities that accompany HD. Therefore, regulating the amounts and activity of the Ask1 protein is a novel strategy for treatment of HD. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.