Genetic Control of Purkinje Cell Degeneration

描述（由申请人提供）：虽然神经退行性疾病是 在老年人群中普遍存在，其分子机制 这些疾病还没有被很好地理解。许多人类神经退行性疾病 有遗传成分，类似地，存在几种突变小鼠品系， 有异常的神经元死亡自发性高脂血症小鼠品系分析 导致特定终末分化细胞死亡的突变 神经元提供了一种方法来识别生存所必需的新分子 成年人大脑中的神经元。存在几种小鼠突变， 胚胎或出生后早期神经元的异常死亡。相比之下，我们 对自发突变粘性（sticky，STI）纯合子小鼠的研究， 表明这种突变导致成年小鼠神经元丢失， 运动缺陷此外，就像影响人类生存的疾病一样， 特定种类的神经元，特定类型的神经元在STI突变体中死亡 小鼠：sti/sti浦肯野细胞的不同亚群在1-2个月时丢失 然后是吻侧颗粒细胞的丧失。 为了开始鉴定sti突变小鼠的分子损伤，我们 将该突变精细定位到8号染色体上的0.17 cM间隔， 产生了一个跨区域的基因组重叠群。此外，通过检查小鼠 该区域的序列和16号染色体上相应的人类序列， 我们已经确定了几个STI基因的候选者，它们存在于 这个基因的最小间隔。此外，我们还发现了一种单基因 近端2号染色体上sti介导的神经变性的遗传抑制因子。 作为理解sti基因在神经元中作用的第一步， 生存，这个应用程序概述了我们的战略，以确定STI基因， 和它的修饰基因Stim这些实验的结果将有助于 这对我们了解人类生存所必需的分子有着重要的意义。 成人大脑中的特定神经元。刺激调节器的识别 基因不仅会给我们更多的了解的分子作用， STI基因产物，但将促进我们对基因调控的理解， 在人类神经退行性疾病中经常观察到表型异质性。

DESCRIPTION (provided by applicant): Although neurodegenerative disorders are prevalent in the aging human population, the molecular mechanisms underlying these diseases are not well understood. Many human neurodegenerative disorders have genetic components and similarly, several mutant mouse strains exist that have abnormal neuronal death. The analysis of mouse strains with spontaneous mutations that result in the death of specific terminally differentiated neurons provides a way to identify novel molecules necessary for the survival of neurons in the adult brain. Several mouse mutations exist that result in the abnormal death of embryonic or early postnatal neurons. In contrast, our studies of mice homozygous for the spontaneous mutation sticky (sti), have shown that this mutation causes neuron loss in adult mice accompanied by locomotor defects. Further, like human disorders which affect the survival of particular classes of neurons, specific types of neurons die in sti mutant mice: Distinct subsets of sti/sti Purkinje cells are lost at 1-2 months followed by the loss of rostral granule cells. To begin the identification of the molecular lesion in sti mutant mice, we have fine mapped the mutation to a 0.17 cM interval on Chromosome 8 and have generated a genomic contig across the region. Further, by examination of mouse sequence from this area and the corresponding human sequence on Chromosome 16, we have identified several candidates for the sti gene that reside within the minimal interval of this gene. In addition, we have identified a monogenic genetic suppressor of sti-mediated neurodegeneration on proximal Chromosome 2. As the first steps in understanding the role of the sti gene in neuron survival, this application outlines our strategy to identify both the sti gene and its modifier gene, Stim. The results of these experiments will contribute significantly to our knowledge of the molecules necessary for survival of specific neurons in the adult brain. The identification of the Stim modifier gene will give us not only additional insight into the molecular action of the sti gene product, but will advance our understanding of genes regulating the phenotypic heterogeneity often observed in human neurodegenerative disorders.