PROPOSED RAT MODEL OF OLIVOPONTOCEREBELLAR ATROPHY

橄榄桥小脑萎缩(OPCA)是一组不同类型的 人和动物的家族性、进行性、神经退行性疾病 这是以小脑不同程度的萎缩为特征的 桥脑和橄榄核。脊髓在以下情况下会受到影响 与脊髓小脑性共济失调(SCA)归为一类。各种基础材料 核团参与OPCA的形式，称为多系统萎缩。 这种疾病存在自发性和遗传性两种形式。模式： 遗传包括常染色体显性遗传和常染色体 隐性和X连锁隐性传递(2、3、10、11)。 在人类的七个不同的基因座上发现了导致SCA的突变(2， 15、17、18、20、22、77)，并包括SCA-1、-3、 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)模仿 人类疾病。柏林Druckrey IV(BD IV)大鼠近交系 早期发病的骨盆肢体共济失调已被确定为可能的新的 OPCA的动物模型，也是本研究的重点。受影响的人 大鼠表现出小脑疾病的迹象，并显示出神经元丢失。 橄榄核。脑干和脊髓中肿胀的轴突含有 明显增加的絮状物的数量表明 微管，如人类疾病(38，40)中描述的那些微管，或 多聚核糖体的数量被夸大。这些老鼠的谱系已经被 通过杂交和回交育种方案建立。 第二代后代的DNA将被检测DNA长度 多态与聚合酶链式反应(PCR)(57)。联动 将使用分析(55)来选择和绘制多态区域 与突变表型相关。YAC克隆与染色体 行走(60)将识别用于研究的目标序列。选定的基因 将被测序，并与正常BD IV大鼠的序列进行比较 确定突变。形态研究将有助于辨别 突变致病机制的研究。这项研究将确定 与这种疾病的遗传有关的潜在遗传区域 在BD IV大鼠和潜在的OPCA自然动物模型中，因此 为人类的评估提供一个候选基因。此外，洞察力 所获得的知识可能会增加对OPCA及其相关疾病的发病机制的了解 人类的精神障碍。

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.