Department of Neurology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, Korea.
Neuroscience. 2009 Nov 10;163(4):1128-34. doi: 10.1016/j.neuroscience.2009.07.048. Epub 2009 Jul 28.
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.
亨廷顿病（HD）的临床特征为舞蹈病、精神障碍和痴呆，而其病理学特征为神经元包含物以及纹状体和皮质的神经退行性变。神经退行性变源于皮质和纹状体中的长投射神经元的丧失。在这项研究中，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 并分析了由此导致的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 末端的 Ask1 抗体阻断 Ask1 活性。抗 Ask1 抗体通过微渗透泵注入 HD 小鼠的纹状体中，持续四周。HD 小鼠中的 Ask1 蛋白和内质网（ER）应激水平增加。失活的 Ask1 与 htt 片段的结合在皮质神经元的细胞质中比核中更为普遍。失活的 Ask1 与 htt 片段的结合阻止了 htt 片段向核内的易位，从而改善了运动功能障碍和萎缩。在正常状态下，活性 Ask1 可能有助于 htt 片段进入核内，而失活的 Ask1 通过与 htt 片段结合而不是将其释放到核内来阻碍这种易位。我们提出，Ask1 可能与 htt 片段相互作用，随后诱导 ER 应激。通过靶向 Ask1 可以防止 BDNF 耗竭；这将减轻 ER 应激，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 的一种新策略。
