Deranged neuronal calcium signaling and Huntington disease

被引：202

作者：

Bezprozvanny, I

Hayden, MR

机构：

[1] Univ Texas, SW Med Ctr, Dept Physiol, Dallas, TX 75390 USA

[2] Univ British Columbia, Womens & Childrens Hosp, Ctr Mol Med & Therapeut, Dept Med Genet, Vancouver, BC V5Z 1M9, Canada

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2004年 / 322卷 / 04期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

calcium signaling; huntingtin; neurodegeneration; polyglutamine expansion; inositol 1,4,5-trisphosphate; NMDA; apoptosis; mitochondria;

D O I：

10.1016/j.bbrc.2004.08.035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1310 / 1317

页数：8

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