Skinner P J, Vierra-Green C A, Clark H B, Zoghbi H Y, Orr H T
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Am J Pathol. 2001 Sep;159(3):905-13. doi: 10.1016/S0002-9440(10)61766-X.
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles contained proteins from the somatodendritic membrane, including mGluR1, GluRDelta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examination of PKCgamma revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKCgamma localization at the Purkinje cell dendritic membrane and decreased detection of PKCgamma by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic membrane trafficking and loss of proteins including PKCgamma, are a part of the neuronal dysfunction in SCA1 transgenic mice.
1型脊髓小脑共济失调（SCA1）是一种神经退行性疾病，由含有扩展型聚谷氨酰胺序列的突变型ataxin-1的表达引起。突变型ataxin-1在转基因小鼠浦肯野细胞中的过表达导致进行性共济失调和浦肯野细胞病变，这与SCA1患者所见的情况非常相似。SCA1小鼠病理学的两个突出方面是细胞质空泡的存在和树突萎缩。我们发现浦肯野细胞中的空泡似乎起源于细胞膜外层的大的内陷。细胞质空泡含有来自体树突膜的蛋白质，包括代谢型谷氨酸受体1（mGluR1）、谷氨酸受体Delta1/Delta2、谷氨酸受体2/3和蛋白激酶C（PKC）γ。对PKCγ的进一步检查发现，其被隔离到细胞质空泡中伴随着PKCγ在浦肯野细胞树突膜上的定位同时丧失，并且通过蛋白质印迹分析检测到的PKCγ减少。此外，空泡对泛素/蛋白酶体降解途径的成分具有免疫反应性。这些发现揭示了SCA1小鼠浦肯野细胞中空泡形成与树突丢失之间的联系，并表明体树突膜运输改变和包括PKCγ在内的蛋白质丢失是SCA1转基因小鼠神经元功能障碍的一部分。
