Polyglutamine diseases represent a family of dominantly inherited neurodegenerative disorders resulting from expansion of a CAG repeat in the coding region of 8 unrelated genes. Expansion of the glutamine tract in the corresponding proteins results in a toxic gain of function. Although the nature of the toxic gain of function and mechanism of cellular pathology are unknown, the nucleus appears to be a key site of cellular pathology for many of these proteins. The focus of the proposed studies is on understanding mechanisms of cellular dysfunction in polyglutamine diseases using as a model, ataxin-3 (AT3), the protein mutated in spinocerebellar ataxia type 3, the most common dominantly inherited ataxia worldwide. Our working hypothesis is that the pathological potential of AT3 is increased by pathophysiological signaling pathways that increase its nuclear localization and by a nuclear specific conformational change that exposes its expanded polyglutamine tract. Using cultures of neurons and other cells we will: 1) characterize nuclear transport of pathological AT3 and its interaction with nuclear transport proteins, 2) define basic parameters of nuclear transport in neurons and characterize pathophysiological signaling pathways that alter nuclear transport of AT3 in neurons, 3) characterize properties of nuclear AT3 and its altered conformation that exposes the polyglutamine domain, and 4) determine effects of AT3 on transcription and the spatial relationship between nuclear Afl and transcription sites. These studies should provide critical information for the field on pathophysiological signaling that regulates nuclear import/export of polyglutamine proteins, the role of the nuclear environment in cellular pathology, the nature of the nuclear specific conformational change that exposes the pathological polyglutamine domain in AT3, and effects of polyglutamine expansion on transcription. These studies should have considerable impact on our understanding of cellular pathology and dysfunction in polyglutamine diseases as well as identifying early events in the disease process that may be targets for therapeutic intervention. In addition to insights into polyglutamine disease pathology, these studies will also generate novel information on nuclear transport in neurons. Nucleocytoplasmic transport is a fundamental and critical process for all cells. No studies have been published on nuclear transport parameters in neurons or neural lines; therefore, all information obtained in these studies on nuclear transport in neurons will be novel and provide initial data needed for future studies. Data generated in these studies should impact several areas of basic and clinical neuroscience.
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