PROPOSED RAT MODEL OF OLIVOPONTOCEREBELLAR ATROPHY

橄榄桥脑小脑萎缩（OPCA）是一个实体在一个不同的群体， 人类和动物的家族性、进行性、神经变性疾病 其特征在于小脑的可变萎缩， 脑桥和橄榄核。 脊髓会受到影响， 与脊髓小脑共济失调（SCA）一起归类。 各种基础 核参与称为多系统萎缩的OPCA形式。 存在自发和遗传形式的疾病。 模式 遗传包括常染色体显性遗传与预期，常染色体 隐性遗传和X连锁隐性遗传（2，3，10，11）。 在人类的七个不同位点发现了导致SCA的突变（2， 15、17、18、20、22、77）并在SCA-1、-3中包括CAG重复扩增， 和-7（15，17，77）。 研究以确定其他形式的突变， OPCA正在进行中。各种动物模型（25、29、30、31、32）模拟 人类疾病一种近交系柏林Druckrey IV（BD IV）大鼠， 早期发生的骨盆肢共济失调已被确定为一种可能的新的 OPCA的动物模型，是本研究的重点。 受影响 大鼠表现出小脑疾病的迹象，并在小脑中表现出神经元损失。 橄榄核 脑干和脊髓中的神经轴突含有 絮状物的数量明显增加，表明 微管，如人类疾病中描述的那些（38，40），或 过量的多核糖体。这些老鼠的谱系已经被 通过交叉-互交和交叉-回交育种方案建立。 将检查第二代子代的DNA长度 聚合酶链反应（PCR）检测多态性（57）。 联动 分析（55）将用于选择和映射多态性区域 与突变体表型相关。 YAC克隆和染色体 步移（60）将识别用于研究的靶序列。选择的基因 将被测序并与正常BD IV大鼠中的那些进行比较， 识别突变。 形态学研究将有助于辨别 突变发病机制。这项研究将确定 与这种疾病的遗传有关的潜在遗传区域 BD IV大鼠和OPCA的潜在天然动物模型，从而 提供了一个候选基因在人的评价。此外，见解 获得的信息可能会增加对OPCA发病机制和相关疾病的认识。 人的紊乱。

Olivopontocerebellar atrophy (OPCA) is one entity in a diverse group of familial, progressive, neurodegenerative disorders in man and animals that is characterized by variable atrophy of the cerebellum, basis pontis, and olivary nuclei. The spinal cord is affected in cases that are grouped with the spinocerebellar ataxias (SCA). Various basal nuclei are involved in forms of OPCA known as multiple system atrophy. Spontaneous and inherited forms of the disease exist. Modes of inheritance include autosomal dominant with anticipation, autosomal recessive, and X-linked recessive transmission (2, 3, 10, 11). Mutations causing SCA have been found at seven different loci in man (2, 15, 17, 18, 20, 22, 77) and include CAG repeat expansion in SCA-1, -3, and -7 (15, 17, 77). Studies to identify mutations in other forms of OPCA are underway. Various animal models (25, 29, 30, 31, 32) mimic human disease. An inbred line of Berlin Druckrey IV (BD IV) rats with early onset of pelvic limb ataxia has been identified as a possible new animal model for OPCA, and is the focus of this study. The affected rats exhibit signs of cerebellar disease and show neuronal loss in the olivary nuclei. Swollen axons in the brainstem and spinal cord contain markedly increased amounts of floccular material suggestive of tangled microtubules, such as those described in human disease (38, 40), or exaggerated amounts of polyribosomes. Pedigrees of these rats have been established by cross-intercross and cross-backcross breeding schemes. The DNA from second generation progeny will be examined for DNA length polymorphism with the polymerase chain reaction (PCR)(57). Linkage analysis (55) will be used to select and map the polymorphic region associated with the mutant phenotype. YAC clones and chromosomal walking(60) will identify the target sequence for study. Selected genes will be sequenced and compared with those in normal BD IV rats to identify the mutation. Morphologic studies will help discern the mechanism of mutation pathogenesis. This study will identify the underlying genetic regions involved in the inheritance of this disorder in BD IV rats and a potential natural animal model for OPCA, and thereby provide a candidate gene for evaluation in man. In addition, insights gained may add to knowledge of pathogenesis of OPCA and related disorders in man.