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Characterization of the structural properties of polyQ proteins accounting for the early neuropathy

Characterization of the structural properties of polyQ proteins accounting for the early neuropathy
Translated Title
초기 신경장애 발병에 중요한 폴리글루타민 단백질의 구조적 특성 분석
Lee, Yun Mi
DGIST Authors
Lee, Yun Mi; Lee, Sung Bae
Lee, Sung Bae
Lee, Kyu Sun
Issue Date
Degree Date
2015. 2
polyglutamine diseasecoiled coil propertynuclear localizationcontinuous glutamineearly neuropathy폴리글루타민 질환감긴 코일 구조핵 내 위치연속적 글루타민초기 신경 장애
Polyglutamine (polyQ) diseases are caused by expansion of glutamine (Q) repeats within the associated protein that induces formation of the intracellular protein aggregates. Collected evidence to date suggests that strong tendency of these mutated proteins toward forming oligo-mers and/or aggregates together with their numerous targets may be the primary cause of the tox-icity causing neuropathy. However, it remains largely unclear what characteristics of the pathogenic polyQ proteins cause these inclusion bodies and how these properties contribute to the various aspects of the disease pathogenesis. Here, we studied what properties of the pathogenic polyQ proteins are primarily associated with the specific early neuropathy, the distal dendrite defects. Different types of structural variants of polyQ proteins had been generated, and only structural variants possessing coiled coil propensity were able to induce the dendrite defects, accompanied by their preferred localization in the nucleus. Given that total mRNA level was decreased by expression of the pathogenic SCA3 accumulated within the nucleus, the observed early neuropathy appeared to be closely associated with the changes in the nuclear transcriptome. Furthermore, we demonstrated that Q continuity within the associated protein is also required for the dendrite abnormalities. In addition, coiled coil property of toxic SCA3 proteins seemed to be critical for interactions with their potential targets as well as their self-aggregation. Taken together, both coiled coil property and Q continuity may be the key contributors necessary for inducing distal dendrite defects caused by pathogenic SCA3. ⓒ 2015 DGIST
Table Of Contents
Ⅰ. INTRODUCTION 1-- Ⅱ. MATERIALS AND METHODS 3-- 2.1. Fly stocks 3-- 2.2. Cell culture and transfection 3-- 2.3. Sample preparation for insoluble aggregated proteins 4-- 2.4. Western blotting 4-- 2.5. Immunostaining 5-- 2.6. Microscope image acquisition 5-- 2.7. mRNA purification 6-- 2.8. Immunoprecipitation 6-- 2.9. Bioinformatics 7-- 2.10. Statistical analysis for significance tes 7-- Ⅲ. RESULTS AND DISCUSSION 8-- 3.1. The coiled coil property of the pathogenic polyQ proteins is essential for the dendrite defects 8-- 3.2. Q continuation is also required for the translocation of pathogenic polyQ pro-teins and inducing of dendrite defects in addition to the coiled coil property 11-- 3.3. The interaction between pathogenic MJD proteins and their potential target proteins within the nucleus seem to be mediated by coiled coil property of pathogenic MJD proteins 13-- Figures and tables 16-- References 35-- Summary in Korean 38-- Acknowledgement 40
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