Deranged neuronal calcium signaling and Huntington disease
Deranged neuronal calcium signaling and Huntington disease
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DOI：
10.1016/j.bbrc.2004.08.035
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发表时间：
2004-10-01
影响因子：
3.1
通讯作者：
Hayden, MR
中科院分区：
文献类型：
--
作者：
Bezprozvanny, I;Hayden, MR
亨廷顿病 (HD) 是一种常染色体显性神经退行性疾病，主要影响中棘纹状体神经元 (MSN)。 HD 是由亨廷顿蛋白 (Htt) 氨基末端区域的聚谷氨酰胺 (polyQ) 扩张 (exp) 引起的。 Htt(exp) 中的 PolyQ 扩展与 MSN 神经变性之间的联系仍然难以捉摸。在这里，我们讨论最近的数据，这些数据将 Htt(exp) 中的 PolyQ 扩展与 MSN 神经元中的 Ca2+ 信号紊乱联系起来。实验证据表明：（1）HD患者淋巴母细胞和YAC72 HD小鼠模型大脑中分离的线粒体中Ca2+稳态异常； (2) Htt(exp) 导致异源表达系统和 YAC72 HD 小鼠模型的 NISN 中 NR1/NR2B NMDA 受体活性增强； (3) Htt(exp) 与 1 型肌醇 1,4,5-三磷酸受体 (InsP(3)R1) 羧基末端结合，并导致 InsP(3)R1 对平面脂质双层和 MSN 中 InsP(3) 的激活敏感。基于这些结果，我们提出 Htt(exp) 诱导的 MSN 胞质和线粒体 Ca2+ 超载在 HD 的发病机制中发挥重要作用，Ca2+ 信号传导阻滞剂可能在 HD 的治疗中发挥有益作用。 (C) 2004 Elsevier Inc. 保留所有权利。
Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Htt(exp) and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Htt(exp) and deranged Ca2+ signaling in MSN neurons. Experimental evidence indicates that (1) Ca2+ homeostasis is abnormal in mitochondria isolated from lymphoblasts of HD patients and from brains of the YAC72 HD mouse model; (2) Htt(exp) leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in NISN from YAC72 HD mouse model; and (3) Htt(exp) binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) carboxy-terminus and causes sensitization of InsP(3)R1 to activation by InsP(3) in planar lipid bilayers and in MSN. Based on these results we propose that Htt(exp)- induced cytosolic and mitochondrial Ca2+ overload of MSN plays an important role in the pathogenesis of HD and that Ca2+ signaling blockers may play a beneficial role in treatment of HD. (C) 2004 Elsevier Inc. All rights reserved.