Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14
Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14
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DOI：
10.1016/j.nbd.2014.06.002
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发表时间：
2014-10-01
影响因子：
6.1
通讯作者：
Kapfhammer, Josef P.
中科院分区：
文献类型：
--
作者：
Ji, Jingmin;Hassler, Melanie L.;Kapfhammer, Josef P.
脊髓小脑共济失调（SCAs）是一种遗传性疾病，可导致浦肯野细胞变性和小脑功能障碍。大多数形式的SCA是由CAG重复扩增引起的，类似于其他多谷氨酰胺疾病，如亨廷顿病。相反，在常染色体显性SCA-14中，该疾病是由蛋白激酶C γ (PKC γ)基因突变引起的，PKC γ基因是小脑浦肯野细胞中一个特征明确的信号分子。因此，SCA-14的研究为揭示最终导致浦肯野细胞功能障碍和变性的分子和病理机制提供了独特的机会。我们已经建立了SCA-14小鼠模型，其中在SCA-14中发现突变的PKC γ蛋白在小脑浦肯野细胞中特异性表达。我们发现，在表达突变PKC γ蛋白的小鼠中，小脑切片培养的浦肯野细胞形态发生了巨大变化，与PKC药理激活后的形态非常相似。在体内转基因幼鼠的小脑局部区域也出现了类似的形态学异常。在成年转基因小鼠中，有证据表明浦肯野细胞的一些局部损失，但没有整体的小脑萎缩。在旋转杆和行走梁上的试验显示转基因小鼠表现出轻度小脑共济失调。我们的研究结果为浦肯野细胞中PKC γ活性的增加和小脑疾病的典型病理变化提供了证据，从而将PKC γ活性的增加和失调与SCA-14和其他形式SCA的小脑疾病的发展紧密联系起来。(C) 2014爱思唯尔公司版权所有。
Spinocerebellar ataxias (SCAs) are hereditary diseases leading to Purkinje cell degeneration and cerebellar dysfunction. Most forms of SCA are caused by expansion of CAG repeats similar to other polyglutamine disorders such as Huntington's disease. In contrast, in the autosomal dominant SCA-14 the disease is caused by mutations in the protein kinase C gamma (PKC gamma) gene which is a well characterized signaling molecule in cerebellar Purkinje cells. The study of SCA-14, therefore, offers the unique opportunity to reveal the molecular and pathological mechanism eventually leading to Purkinje cell dysfunction and degeneration. We have created a mouse model of SCA-14 in which PKC gamma protein with a mutation found in SCA-14 is specifically expressed in cerebellar Purkinje cells. We find that in mice expressing the mutated PKC gamma protein the morphology of Purkinje cells in cerebellar slice cultures is drastically altered and mimics closely the morphology seen after pharmacological PKC activation. Similar morphological abnormalities were seen in localized areas of the cerebellum of juvenile transgenic mice in vivo. In adult transgenic mice there is evidence for some localized loss of Purkinje cells but there is no overall cerebellar atrophy. Transgenic mice show a mild cerebellar ataxia revealed by testing on the rotarod and on the walking beam. Our findings provide evidence for both an increased PKC gamma activity in Purkinje cells in vivo and for pathological changes typical for cerebellar disease thus linking the increased and dysregulated activity of PKC gamma tightly to the development of cerebellar disease in SCA-14 and possibly also in other forms of SCA. (C) 2014 Elsevier Inc. All rights reserved.