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Kwon, Min Jee,Han, Myeong Hoon,Bagley, Joshua A.,Hyeon, Do Young,Ko, Byung Su,Lee, Yun Mi,Cha, In Jun,Kim, Seung Yeol,Kim, Dong Young,Kim, Ho Min,Hwang, Daehee,Lee, Sung Bae,Jan, Yuh Nung National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.45
<P><B>Significance</B></P><P>It remains unclear how the structural properties of polyglutamine (polyQ) proteins, which underlie several neurodegenerative disorders, including Huntington’s disease and spinocerebellar ataxias (SCAs), translate into the toxicity of these proteins. Here, we demonstrate that coiled-coil structures in expanded polyQ regions of SCA type 3 (SCA3) proteins cause dendrite defects in <I>Drosophila</I> neurons, as well as behavioral abnormalities. Moreover, interactions of SCA3 with Foxo mediated by coiled-coil domains of these two proteins resulted in functional impairment of this transcription factor, whereas its overexpression significantly rescued the SCA3-induced defects. Our study expanded the current understanding of neuronal pathology mediated by polyQ proteins via the coiled-coil–mediated interactions. These results may have important implications in therapeutic strategies for polyQ protein-related diseases.</P><P>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 <I>Drosophila</I> neurons. To functionally characterize coiled-coil structures in the Q repeat regions, we generated three structural variants of SCA3 polyQ proteins: (<I>i</I>) MJDtr-76Q, containing both α-helical coiled-coil and β-sheet hairpin structures in the Q repeat region; (<I>ii</I>) 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 (<I>iii</I>) 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 <I>Drosophila</I> 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 <I>Drosophila</I>. 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.</P>