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Coiled coil structure-dependent interactions between polyQ proteins and Foxo contribute to dendrite defects
- Coiled coil structure-dependent interactions between polyQ proteins and Foxo contribute to dendrite defects
- Kwon, Min Jee; Han, Myeong Hoon; Joshua A. Bagley; Hyeon, Do Young; Ko, Byung Su; Lee, Yun Mi; Cha, InJun; Kim, SeungYeol; Kim, Dong Young; Kim, Ho Min; Hwang, Daehee; Lee, Sung-Bae; Yuh Nung Jan
- DGIST Authors
- Hwang, Daehee; Lee, Sung-Bae
- Issue Date
- 8th BCS Student Symposium
- Neurodegenerative disorders, such as Huntington's diseases and spinocerebellar ataxias (SCAs), are driven by proteins with expanded polyglutamine (polyQ) tracts. Recently, coiled-coil structures in polyQ regions of such proteins were shown to facilitate aggregate formation and ultimately lead to cell death. However, the molecular mechanism linking these structural domains to neuronal toxicity of polyQ proteins remains elusive. Here, we demonstrate that coiled-coil structures in the Q repeat region of SCA type 3 (SCA3) polyQ proteins confer protein toxicity in Drosophila neurons. To functionally characterize coiled-coil structures in the Q repeat regions, we generated three structural variants of SCA3 polyQ proteins: (i) MJDtr-76Q, containing both α-helical coiled-coil and β-sheet hairpin structures in the Q repeat region; (ii) MJDtr-70Q_cc0, possessing only α-helical coiled-coil structures due to the incorporation of β-sheet-breaking residues (Q-to-N or Q-to-E mutations); and (iii) MJDtr-70Q_pQp, with no secondary structure due to the introduced proline residues (Q-to-P mutations). Through comparative analysis of these variants, we found that coiled-coil structures facilitated nuclear localization of SCA3 polyQ proteins and induced dendrite defects in Drosophila dendritic arborization neurons. Furthermore, genetic and functional screening identified the transcription factor Foxo as a target of polyQ proteins, and coiled-coil-mediated interactions of Foxo and polyQ proteins in the nucleus resulted in the observed dendrite and behavioral defects in Drosophila These results demonstrate that coiled-coil structures of polyQ proteins are crucial for their neuronal toxicity, which is conferred through coiled-coil to coiled-coil interactions with the nuclear targets of these proteins.
- DGIST dept. of Brain & Cognitive Sciences
- Related Researcher
Lee, Sung Bae
Laboratory of Neurodegenerative Diseases and Aging
Cellular mechanism of neurodegenerative diseases; Neuronal maintenance and remodeling; 퇴행성 뇌질환의 세포기전; 신경계 유지 및 리모델링 연구
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- Department of New BiologySystems Biology and Medicine Lab2. Conference Papers
Department of Brain SciencesLaboratory of Neurodegenerative Diseases and Aging2. Conference Papers
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