Attractin and Mahoganoid in Spongy Neurodegeneration

Attractin 和 Mahoganoid 在海绵状神经变性中的作用

• 批准号: 6704719
• 负责人: Gregory Stefan Barsh
• 金额: $ 33.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704719
• 关键词: electron microscopy; gene mutation; gene targeting; genetic disorder; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; microarray technology; neural degeneration; neuropathology; prions; proteasome; protein metabolism; spongiform encephalopathy; ubiquitin; yeast two hybrid system

DESCRIPTION (provided by applicant): Spongiform degeneration of the central nervous system is best known as the hallmark of prions, but despite a tremendous body of knowledge regarding the molecular genetics and biochemistry of PrP, the pathophysiologic mechanisms of vacuolation and neuronal cell death are still unknown. We have recently identified two genes in mice, Attractin (Atrn) and Mahoganoid, in which loss-of-function mutations cause recessive inheritance of a neurodegenerative disease whose manifestations are remarkably similar to those caused by gain-of-function mutations in PrP. Both genes were identified because they are also previously existing mouse coat color mutations (Atrn was formerly known as mahogany); studies from our laboratory based on the genetics of pigmentation suggest that Atrn and Mahoganoid are part of a conserved biochemical and cellular pathway that controls ubiquitination and proteasomal degradation. We propose a series of experiments to gain further insight into the pathophysiology of spongiform degeneration in Atrn and Mahoganoid mutant mice, and its relationship to PrP metabolism. Brain sections and homogenates from Atrn and Mahoganoid mutant animals will be examined for evidence of PrP aggregates and proteasomal dysfunction, and genetic and biochemical interaction studies will be carried out to test if neurodegeneration in Atrn or Mahoganoid mutant animals is caused by abnormalities in the production or processing of PrP. A transgenic assay will be developed to assess which domains of Mahoganoid are required to prevent neurodegeneration, and cell biologic studies will be applied to investigate whether Atrn and mahoganoid act in a common subcellular location or share intracellular interaction partners. Finally, the potential for additional or redundant roles in the Atrn-Mahoganoid pathway will be explored by investigating paralogs for each gene. Investigating the biochemical, cellular, and genetic relationships between Atrn, Mahoganoid, and PrP is likely to provide general insight into the pathogenesis of spongy degeneration.

描述（由申请人提供）：中枢神经系统的海绵状变性是朊病毒的标志，但尽管关于PrP的分子遗传学和生物化学有大量的知识，但空泡化和神经元细胞死亡的病理生理机制仍然未知。我们最近在小鼠中发现了两个基因，Attractin（Atrn）和Mahoganoid，其中功能丧失突变导致神经退行性疾病的隐性遗传，其表现与PrP中功能获得突变引起的表现非常相似。这两个基因被确定，因为它们也是以前存在的小鼠毛色突变（Atrn以前被称为桃花心木）;我们实验室基于色素沉着遗传学的研究表明，Atrn和Mahoganoid是控制泛素化和蛋白酶体降解的保守生化和细胞途径的一部分。我们提出了一系列的实验，以进一步了解Atrn和Mahoganoid突变小鼠海绵状变性的病理生理学，及其与PrP代谢的关系。将检查Atrn和Mahoganoid突变动物的脑切片和匀浆是否存在PrP聚集体和蛋白酶体功能障碍的证据，并进行遗传和生化相互作用研究，以检测Atrn或Mahoganoid突变动物的神经变性是否由PrP产生或加工异常引起。将开发一种转基因测定法来评估Mahoganoid的哪些结构域是防止神经变性所必需的，并将应用细胞生物学研究来研究Atrn和Mahoganoid是否在共同的亚细胞位置起作用或共享细胞内相互作用伴侣。最后，通过研究每个基因的旁系同源物，将探索Atrn-Mahoganoid途径中额外或冗余作用的潜力。研究Atrn、Mahoganoid和PrP之间的生物化学、细胞和遗传关系可能为海绵变性的发病机制提供一般性见解。