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dc.contributor.advisor 이성배 -
dc.contributor.author Kwon, Min Jee -
dc.date.accessioned 2019-10-02T16:00:18Z -
dc.date.available 2020-02-28T09:21:30Z -
dc.date.issued 2019 -
dc.identifier.uri http://dgist.dcollection.net/common/orgView/200000171523 en_US
dc.identifier.uri http://hdl.handle.net/20.500.11750/10673 -
dc.description.abstract Neurodegenerative diseases are characterized by accumulation of misfolded proteins that have a strong tendency to form insoluble oligomers and aggregates inside and/or outside of the afflicted neurons. Such accumulation is known to confer protein toxicity that causes various neuropathic features such as dendrite defects in the neurodegenerative diseases. Although extensive studies have speculated that disease-responsible proteins are deeply associated with perturbation of proper neuronal morphology and functions, the detailed mechanism of how these toxic proteins resulting in these deleterious outcomes of neuronal defects is still yet to be elucidated. Polyglutamine (polyQ) diseases are inherent, autosomal dominant neurodegenerative diseases that are caused by the expansion of the CAG (encoding glutamine) repeats within the coding sequence of the disease genes. Recently, the importance of coiled coil structures in polyQ regions of such proteins in formation of insoluble aggregates and ultimate event of cell death is highlighted. However, it remains elusive how the structural properties of polyQ proteins translate into protein toxicity. In order to functionally characterize coiled coil structures in the expanded polyQ regions, transgenic fly lines expressing the following three structural variants of spinocerebellar ataxia type-3 (SCA3 -
dc.description.abstract also known as Machado-Joseph disease (MJD)) proteins were generated: 1) MJDtr-76Q having both α-helical coiled coil and β-sheet hairpin structures, 2) MJDtr-70Q_cc0 having only α-helical coiled coil structures and lacking β-sheet motifs, and 3) MJDtr-70Q_pQp with no secondary structure. Here, I demonstrate that coiled coil structures in the expanded polyQ regions of MJD proteins facilitate nuclear localization of polyQ proteins and contribute to dendrite defects in Drosophila neurons, as well as behavioral abnormalities. Furthermore, in this study, the transcriptional factor Foxo is identified as a novel target of MJD polyQ proteins. Moreover, I reveal that interactions of Foxo and polyQ proteins are mediated by coiled coil domains of these two proteins, resulting in functional impairment of Foxo that contributes to dendrite and behavioral defects. This study expands the current understanding of polyQ-induced neuronal pathology via the coiled coil-mediated interactions and may have important implications in therapeutic strategies for polyQ protein-related diseases. -
dc.description.statementofresponsibility open -
dc.description.tableofcontents List of Contents

Abstract i
List of contents ii
List of tables iv
List of figures v



I. Introduction 1
1.1 Protein toxicity in neurodegenerative diseases causes early neuropathic features such as dendrite defects 1
1.2 PolyQ diseases are suitable models to study associations of protein toxicity and dendrite pathology 3
1.3 Dendrite defects induced by pathogenic polyQ proteins are deeply associated with loss of Golgi outposts and decreased plasma membrane supply 7
1.4 Structural understanding of pathogenic polyQ proteins are critical to understand polyQ pathology 10

II. Materials and Methods 12

III. Results 24
3.1 Coiled coil structures in the Q repeat region of SCA3 polyQ proteins contribute to dendrite defects 24
3.2 Coiled coil structures of SCA3 polyQ proteins promote their nuclear localization 42
3.3 Interaction of Forkhead box, sub-group O (Foxo) with SCA3 polyQ proteins in the nucleus leads to its functional impairment and ensuing dendrite defects 50
3.4 Coiled coil domains of Foxo are required for its interaction with SCA3 polyQ proteins 66
3.5 Foxo overexpression restores the behavioral defects induced by coiled coil structure-mediated polyQ protein toxicity 79
3.6 Coiled coil structure-mediated target sequestration affinity of polyQ proteins strongly correlates with polyQ-induced dendrite defects 92

IV. Discussions 104

V. References 113

VI. Summary in Korean 122
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dc.format.extent 141 -
dc.language eng -
dc.publisher DGIST -
dc.source /home/dspace/dspace53/upload/200000171523.pdf -
dc.title Coiled coil structure-mediated interactions between polyQ proteins and Foxo contribute to polyQ-induced defects in Drosophila -
dc.type Thesis -
dc.identifier.doi 10.22677/thesis.200000171523 -
dc.description.degree DOCTOR -
dc.contributor.department Brain and Cognitive Sciences -
dc.contributor.coadvisor Kim, Tae Soo -
dc.date.awarded 2019-02 -
dc.publisher.location Daegu -
dc.description.database dCollection -
dc.citation XT.BD 권38 201902 -
dc.date.accepted 2019-01-30 -
dc.contributor.alternativeDepartment 뇌인지과학전공 -
dc.embargo.liftdate 2019-01-30 -
dc.contributor.affiliatedAuthor Lee, Sung Bae -
dc.contributor.affiliatedAuthor Kwon, Min Jee -
dc.contributor.affiliatedAuthor Kim, Tae Soo -
dc.contributor.alternativeName 김태수 -
dc.contributor.alternativeName 권민지 -
dc.contributor.alternativeName Lee, Sung Bae -
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