Genetic Control of Purkinje Cell Degeneration

描述(申请人提供)：虽然神经退行性疾病 在老龄化人口中普遍存在，其背后的分子机制 人们对这些疾病还没有很好的了解。许多人类神经退行性疾病 有遗传成分，类似地，存在几个突变的小鼠品系 有异常的神经元死亡。自发性小鼠品系的分析 导致特定终末分化细胞死亡的突变 神经元提供了一种识别生存所需的新分子的方法 成人大脑中的神经元。存在几种小鼠突变，导致 胚胎或出生后早期神经元的异常死亡。相比之下，我们的 小鼠自发突变粘性(STI)纯合子的研究 研究表明，这种突变会导致成年小鼠神经元丢失，并伴随着 运动性缺陷。此外，就像影响人类生存的人类疾病一样 特定类别的神经元，特定类型的神经元在sti突变中死亡 小鼠：不同的STI/STI浦肯野细胞亚群在1-2个月时丢失 随之而来的是吻端颗粒细胞的丢失。 为了开始鉴定sti突变小鼠的分子损伤，我们有 精细地将突变定位在8号染色体上0.17 cM的间隔，并 在整个区域产生了基因组重叠群。此外，通过对小鼠的检查， 来自该区域的序列和16号染色体上相应的人类序列， 我们已经确定了几个sti基因的候选基因，这些候选基因位于 该基因的最小间隔。此外，我们还发现了一种单基因 STI介导的近端2号染色体上神经变性的遗传抑制。 作为了解sti基因在神经元中的作用的第一步 生存，这个应用程序概述了我们识别sti基因的策略 以及它的修饰基因STIM。这些实验的结果将有助于 重要的是我们对生存所需的分子的了解 成人大脑中的特定神经元。STIM修饰语的识别 基因不仅会让我们更深入地了解基因的分子作用 STI基因产物，但将促进我们对调控基因的理解 在人类神经退行性疾病中经常观察到表型的异质性。

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.