Attractin and Mahoganoid in Spongy Neurodegeneration

描述(申请人提供)：中枢神经系统的海绵状变性最为人所知的是PrP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，但空泡化和神经细胞死亡的病理生理学机制仍不清楚。我们最近在小鼠身上发现了两个基因，Attractin(Atrn)和Mahoganid，其中功能丧失突变会导致一种神经退行性疾病的隐性遗传，其表现与PrP功能获得突变引起的疾病非常相似。之所以确定这两个基因，是因为它们也是先前存在的小鼠被毛颜色突变(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Mahoganid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。我们提出了一系列实验，以进一步了解Atrn和Mahoganid突变小鼠海绵状变性的病理生理机制，以及它与PrP代谢的关系。将检查来自Atrn和Mahoganid突变动物的脑切片和匀浆，以寻找PrP聚集体和蛋白酶体功能障碍的证据，并将进行遗传和生化相互作用研究，以测试Atrn或Mahoganid突变动物的神经退化是否由PrP的生产或加工异常引起。将开发一种转基因试验来评估哪些结构域是防止神经退化所必需的，并将应用细胞生物学研究来调查Atrn和mahoganid是在共同的亚细胞位置上发挥作用，还是共享细胞内相互作用伙伴。最后，将通过研究每个基因的Paralog来探索Atrn-Mahoganid途径中额外或多余角色的可能性。研究Atrn、Mahoganid和PrP之间的生化、细胞和遗传关系可能为海绵状变性的发病机制提供全面的见解。

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.