O'Hearn Elizabeth E, Hwang Hyon S, Holmes Susan E, Rudnicki Dobrila D, Chung Daniel W, Seixas Ana I, Cohen Rachael L, Ross Christopher A, Trojanowski John Q, Pletnikova Olga, Troncoso Juan C, Margolis Russell L
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Mov Disord. 2015 Nov;30(13):1813-1824. doi: 10.1002/mds.26348. Epub 2015 Sep 4.
SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration.
A fixed SCA12 brain was examined using gross, microscopic, and immunohistochemical methods. The effect of the repeat expansion on PPP2R2B Bβ1 expression was examined in multiple cell types by transient transfection of constructs containing the PPP2R2B Bβ1 promoter region attached to a luciferase reporter. The neurotoxic effect of PPP2R2B overexpression was examined in transfected rat primary neurons.
Neuropathological investigation revealed enlarged ventricles, marked cerebral cortical atrophy and Purkinje cell loss, less-prominent cerebellar and pontine atrophy, and neuronal intranuclear ubiquitin-positive inclusions, consistent with Marinesco bodies, which did not stain for long polyglutamine tracts, alpha-synuclein, tau, or transactive response DNA-binding protein 43. Reporter assays demonstrated that the region of PPP2R2B containing the repeat functions as a promoter, and that promoter activity increases with longer repeat length and is dependent on cell type, repeat sequence, and sequence flanking the repeat. Overexpression of PPP2R2B in primary cortical neurons disrupted normal morphology.
SCA12 involves extensive, but selective, neurodegeneration distinct from Alzheimer's disease, synucleinopathies, tauopathies, and glutamine expansion diseases. SCA12 neuropathology may arise from the neurotoxic effect of repeat-expansion-induced overexpression of PPP2R2B.
脊髓小脑共济失调12型（SCA12）是一种进行性常染色体显性疾病，由5号染色体q32区域PPP2R2B基因中的CAG/CTG重复序列扩增引起，其特征为震颤、步态共济失调、反射亢进、辨距不良、眼球运动异常、焦虑、抑郁，有时还伴有认知障碍。神经影像学检查已证实存在小脑和皮质萎缩。我们现展示首例经尸检的SCA12患者脑的神经病理学特征，并利用细胞模型来阐明SCA12神经变性的潜在机制。
使用大体、显微镜及免疫组织化学方法检查固定的SCA12患者脑。通过瞬时转染含有与荧光素酶报告基因相连的PPP2R2B Bβ1启动子区域的构建体，在多种细胞类型中检测重复序列扩增对PPP2R2B Bβ1表达的影响。在转染的大鼠原代神经元中检测PPP2R2B过表达的神经毒性作用。
神经病理学研究显示脑室扩大、明显的大脑皮质萎缩和浦肯野细胞丢失、小脑和脑桥萎缩不明显，以及神经元核内泛素阳性包涵体，与马里内斯科小体一致，该包涵体对长聚谷氨酰胺链、α-突触核蛋白、tau或反式激活反应DNA结合蛋白43均不着色。报告基因检测表明，PPP2R2B中包含重复序列的区域具有启动子功能，且启动子活性随重复序列长度增加而增强，并取决于细胞类型、重复序列及重复序列两侧的序列。PPP2R2B在原代皮质神经元中的过表达破坏了正常形态。
SCA12涉及广泛但具有选择性的神经变性，与阿尔茨海默病、突触核蛋白病、tau蛋白病及谷氨酰胺扩增疾病不同。SCA12的神经病理学可能源于重复序列扩增诱导的PPP2R2B过表达所产生的神经毒性作用。
