TY - JOUR
T1 - Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity
AU - Branco-Santos, Joana
AU - Herrera, Federico
AU - Poças, Gonçalo M.
AU - Pires-Afonso, Yolanda
AU - Giorgini, Flaviano
AU - Domingos, Pedro M.
AU - Outeiro, Tiago F.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85030697664&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddx260
DO - 10.1093/hmg/ddx260
M3 - Article
C2 - 28934390
AN - SCOPUS:85030697664
SN - 0964-6906
VL - 26
SP - 3763
EP - 3775
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 19
ER -