Jeub Monika, Herbst Martin, Spauschus Alexander, Fleischer Henrik, Klockgether Thomas, Wuellner Ullrich, Evert Bernd O
Department of Neurology, University of Bonn Medical Center, Sigmund Freud-Strasse 25, D-53105 Bonn, Germany.
Exp Neurol. 2006 Sep;201(1):182-92. doi: 10.1016/j.expneurol.2006.03.029. Epub 2006 Jun 12.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-3. There is growing evidence that neuronal electrophysiological properties are altered in a variety of polyglutamine diseases such as Huntington's disease and SCA1 and that these alterations may contribute to disturbances of neuronal function prior to neurodegeneration. To elucidate possible electrophysiological changes in SCA3, we generated a stable PC12 cell model with inducible expression of normal and mutant human full-length ataxin-3 and analyzed the electrophysiological properties after induction of the recombinant ataxin-3 expression. Neuronally differentiated PC12 cells expressing the expanded form of ataxin-3 showed significantly decreased viabilities and developed ultrastructural changes resembling human SCA3. Prior to neuronal cell death, we found a significant reduction of the resting membrane potential and a hyperpolarizing shift of the activation curve of the delayed rectifier potassium current. These findings indicate that electrophysiological properties are altered in mutant ataxin-3 expressing neuronal cells and may contribute to neuronal dysfunction in SCA3.
3型脊髓小脑共济失调（SCA3）是一种常染色体显性遗传的神经退行性疾病，由疾病蛋白ataxin-3内的多聚谷氨酰胺重复序列扩增引起。越来越多的证据表明，在多种多聚谷氨酰胺疾病（如亨廷顿舞蹈症和SCA1）中，神经元的电生理特性发生了改变，并且这些改变可能在神经退行性变之前就导致了神经元功能紊乱。为了阐明SCA3可能存在的电生理变化，我们构建了一个稳定的PC12细胞模型，可诱导表达正常和突变的人全长ataxin-3，并在诱导重组ataxin-3表达后分析其电生理特性。表达ataxin-3扩增形式的神经元分化PC12细胞显示活力显著降低，并出现类似于人类SCA3的超微结构变化。在神经元细胞死亡之前，我们发现静息膜电位显著降低，延迟整流钾电流的激活曲线发生超极化偏移。这些发现表明，表达突变ataxin-3的神经元细胞的电生理特性发生了改变，可能导致SCA3中的神经元功能障碍。
