Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3.
Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3.
复制标题
DOI：
10.1523/jneurosci.3909-08.2008
复制
发表时间：
2008-11-26
期刊：
影响因子：
--
通讯作者：
Bezprozvanny I
中科院分区：
文献类型：
--
作者：
Chen X;Tang TS;Tu H;Nelson O;Pook M;Hammer R;Nukina N;Bezprozvanny I
脊髓小脑型共济失调3型(SCA3)，又称马查多-约瑟夫病(MJD)，是一种常染色体显性遗传性神经退行性疾病，由ATX3、MJD1蛋白多聚谷氨酰胺扩张引起。在生化实验中，我们证明了突变的ATX3exp与细胞内钙离子释放通道--1型三磷酸肌醇受体(InsP3R1)特异相关。在电生理和钙离子成像实验中，我们发现在突变体ATX3exp存在的情况下，InsP3R1被InsP3激活。我们发现，给SCA3-YAC-84Q转基因小鼠喂食丹曲林--一种临床上相关的细胞内钙信号稳定剂--可以改善它们的运动能力，并防止桥核和黑质区域的神经细胞丢失。提示钙信号转导紊乱在SCA3发病机制中可能起重要作用，丹曲林等钙信号稳定剂有望成为治疗SCA3患者的潜在药物。
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in ataxin-3 (ATX3, MJD1) protein. In biochemical experiments we demonstrate that mutant ATX3exp specifically associated with the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), an intracellular calcium (Ca2+) release channel. In electrophysiological and Ca2+ imaging experiments we show that InsP3R1 was sensitized to activation by InsP3 in the presence of mutant ATX3exp. We found that feeding SCA3-YAC-84Q transgenic mice with dantrolene, a clinically relevant stabilizer of intracellular Ca2+ signaling, improved their motor performance and prevented neuronal cell loss in pontine nuclei and substantia nigra regions. Our results indicate that deranged Ca2+ signaling may play an important role in SCA3 pathology and that Ca2+ signaling stabilizers such as dantrolene may be considered as potential therapeutic drugs for treatment of SCA3 patients.