UBIQUITIN DEFICIENCY IN AGING AND NEURODEGENERATION

描述(由申请人提供)： 泛素蛋白酶体系统(UPS)是真核细胞降解不需要的蛋白质的主要机制。UPS在保护细胞免受环境对蛋白质的破坏以及产生含有错误的多肽的潜在有害后果方面发挥了重要作用。据报道，在正常衰老和许多迟发性神经退行性疾病的发病机制中，UPS特定元件的活性下降。尽管有诱人的遗传证据将帕金森氏症等神经退行性疾病与UPS组件中的特定损伤联系起来，但这种蛋白分解系统在维持完整动物的蛋白质动态平衡和抵抗应激方面的作用从未被研究过。这项拟议的探索性项目旨在创造在诱导泛素表达能力方面存在缺陷的小鼠系，泛素是UPS应对压力的关键步骤。带有两个多泛素基因Ubb和Ubc缺失的小鼠将被培育并杂交，以产生含有逐渐严重的泛素缺乏症的品系。这些泛素缺陷小鼠的寿命以及发育、神经、行为和生长表型将受到密切监测。将评估泛素缺乏对环境神经毒素敏感性的影响。最后，这些小鼠将与C57BL/6小鼠回交，产生适合用已建立的和新兴的衰老和神经退化模型进行育种的同源品系。

DESCRIPTION (provided by applicant): The ubiquitin proteasome system (UPS) is the principal mechanism for degrading unwanted proteins in eukaryotic cells. The UPS contributes an important role in protecting cells against stress resulting from environmental damage to proteins and against the potentially deleterious consequences of the production of error-containing polypeptides. A decline in activity of specific elements of the UPS has been reported to occur during normal aging and in the pathogenesis of many late-onset neurodegenerative diseases. Despite tantalizing genetic evidence linking neurodegenerative diseases like Parkinson's to specific lesions in components of the UPS, the role of this proteolytic system in maintaining protein homeostasis and resisting stress in intact animals has never been studied. The proposed exploratory project aims to create mouse lines that are defective in the ability to induce expression of ubiquitin, a key step in the UPS, in response to stress. Mice harboring deletions of the two polyubiquitin genes, UbB and UbC will be bred and intercrossed to produce lines containing progressively severe ubiquitin deficiencies. These ubiquitin-deficient mice will be closely monitored for life-span, as well as developmental, neurological, behavioral and growth phenotypes. The effect of ubiquitin deficiency on the sensitivity to environmental neurotoxins will be evaluated. Finally these mice will be backcrossed with C57BL/6 mice to generate congenic lines suitable for breeding with established and emerging models of aging and neurodegeneration.