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Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

© The Author 2017. Published by Oxford University Press. All rights reserved. Huntington's disease 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 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 Huntington's disease.

Publication metadata

Author(s): Branco-Santos J, Herrera F, Pocas GM, Pires-Afonso Y, Giorgini F, Domingos PM, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2017

Volume: 26

Issue: 19

Pages: 3763-3775

Print publication date: 01/10/2017

Online publication date: 07/07/2017

Acceptance date: 30/06/2017

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddx260

DOI: 10.1093/hmg/ddx260

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