UBIQUITIN DEFICIENCY IN AGING AND NEURODEGENERATION

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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.