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

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3763-3775
Number of pages13
JournalHuman molecular genetics
Volume26
Issue number19
DOIs
Publication statusPublished - 1 Oct 2017

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