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Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity

Joana Branco-Santos, Federico Herrera, Gonçalo M. Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M. Domingos, Tiago F. Outeiro
doi: https://doi.org/10.1101/135954
Joana Branco-Santos
1Laboratory of Cell Structure and Dynamics, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
2Laboratory of Cell Signaling in Drosophila, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
3Department of Genetics, University of Leicester, Leicester, United Kingdom
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Federico Herrera
1Laboratory of Cell Structure and Dynamics, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
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  • For correspondence: touteir@gwdg.de fherrera@itqb.unl.pt domingp@itqb.unl.pt
Gonçalo M. Poças
2Laboratory of Cell Signaling in Drosophila, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
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Yolanda Pires-Afonso
2Laboratory of Cell Signaling in Drosophila, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
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Flaviano Giorgini
3Department of Genetics, University of Leicester, Leicester, United Kingdom
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Pedro M. Domingos
2Laboratory of Cell Signaling in Drosophila, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
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  • For correspondence: touteir@gwdg.de fherrera@itqb.unl.pt domingp@itqb.unl.pt
Tiago F. Outeiro
4Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Gottingen, Göttingen, Germany
5Max Planck Institute for Experimental Medicine, Göttingen, Germany
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  • For correspondence: touteir@gwdg.de fherrera@itqb.unl.pt domingp@itqb.unl.pt
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Abstract

Huntington’s disease (HD) is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregation and toxicity in human cells and Drosophila neurons. We used bimolecular fluorescence complementation (BiFC) to show that expression of single phosphomimic mutations completely abolished HTTex1 aggregation in human cells. In Drosophila, Mimicking phosphorylation at T3 decreased HTTex1 aggregation both in larvae and adult flies. Interestingly, pharmacological or genetic inhibition of protein phosphatase 1 (PP1) prevented HTTex1 aggregation in both human cells and Drosophila while increasing neurotoxicity in flies. Our findings suggest that PP1 modulates HTTex1 aggregation by regulating phosphorylation on T3. In summary, our study suggests that modulation of HTTex1 single phosphorylation events by PP1 could constitute an efficient and direct molecular target for therapeutic interventions in HD.

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Posted May 10, 2017.
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Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity
Joana Branco-Santos, Federico Herrera, Gonçalo M. Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M. Domingos, Tiago F. Outeiro
bioRxiv 135954; doi: https://doi.org/10.1101/135954
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Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity
Joana Branco-Santos, Federico Herrera, Gonçalo M. Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M. Domingos, Tiago F. Outeiro
bioRxiv 135954; doi: https://doi.org/10.1101/135954

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