Cited 14 time in webofscience Cited 19 time in scopus

Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects

Title
Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects
Authors
Kwon, Min JeeHan, Myeong HoonBagley, Joshua A.Hyeon, Do YoungKo, Byoung SuLee, Yun MiCha, In JunKim, Seung YeolKim, Dong YoungKim, Ho MinHwang, DaeheeLee, Sung-BaeJan, Yuh Nung
DGIST Authors
Hwang, Daehee; Lee, Sung-Bae
Issue Date
2018-11
Citation
Proceedings of the National Academy of Sciences of the United States of America, 115(45), E10748-E10757
Type
Article
Article Type
Article
Keywords
polyQcoiled coilFoxodendritesneurodegenerative diseases
ISSN
0027-8424
Abstract
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. © 2018 BioMed Central Ltd..All right reserved.
URI
http://hdl.handle.net/20.500.11750/9412
DOI
10.1073/pnas.1807206115
Publisher
National Academy of Sciences
Related Researcher
  • Author Lee, Sung Bae Laboratory of Neurodegenerative Diseases and Aging
  • Research Interests Cellular mechanism of neurodegenerative diseases; Neuronal maintenance and remodeling; 퇴행성 뇌질환의 세포기전; 신경계 유지 및 리모델링 연구
Files:
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Collection:
Department of New BiologySystems Biology and Medicine Lab1. Journal Articles
Department of Brain and Cognitive SciencesLaboratory of Neurodegenerative Diseases and Aging1. Journal Articles


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