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

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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 alpha-helical coiled-coil and beta-sheet hairpin structures in the Q repeat region; (ii) MJDtr70Q_cc0, possessing only alpha-helical coiled-coil structures due to the incorporation of beta-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.
Publisher
NATL ACAD SCIENCES
Issue Date
2018-11
Language
English
Article Type
Article
Keywords

HUNTINGTONS-DISEASE; TRANSCRIPTION FACTOR; POLYGLUTAMINE PROTEIN; DROSOPHILA; NEURONS; AGGREGATION; DEGENERATION; MECHANISMS; CHAPERONES; RECEPTORS

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.115, no.45, pp.E10748 - E10757

ISSN
0027-8424
DOI
10.1073/pnas.1807206115
URI
http://hdl.handle.net/10203/247118
Appears in Collection
MSE-Journal Papers(저널논문)
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