PT  - JOURNAL ARTICLE
AU  - Joana Branco-Santos
AU  - Federico Herrera
AU  - Gonçalo M. Poças
AU  - Yolanda Pires-Afonso
AU  - Flaviano Giorgini
AU  - Pedro M. Domingos
AU  - Tiago F. Outeiro
TI  - Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity
AID  - 10.1101/135954
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 135954
4099  - http://biorxiv.org/content/early/2017/05/10/135954.short
4100  - http://biorxiv.org/content/early/2017/05/10/135954.full
AB  - 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.