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|Title:||Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity|
Poças, Gonçalo M.
Domingos, Pedro M.
Outeiro, Tiago F.
|Publisher:||Oxford University Press (OUP)|
|Citation:||Human Molecular Genetics, 2017, ddx260|
|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.|
|Embargo on file until:||7-Jul-2018|
|Rights:||Copyright © 2017, Oxford University Press (OUP). Deposited with reference to the publisher’s open access archiving policy.|
|Description:||The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.|
|Appears in Collections:||Published Articles, Dept. of Genetics|
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|Branco-Santos Complete accepted version.pdf||Post-review (final submitted author manuscript)||16.45 MB||Adobe PDF||View/Open|
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