journal contribution posted on 06.07.2017, 14:40 by Joana Branco-Santos, Federico Herrera, Gonçalo M. Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M. Domingos, Tiago F. Outeiro
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
The authors thank the Bloomington Drosophila Stock Center and the
Developmental Studies Hybridoma Bank for fly stocks and antibodies, respectively.
The authors also thank Bioimaging Unit from Instituto de Medicina Molecular and
Advance Imaging Unit from Gulbenkian Science Institute for support with imaging.
TFO and FH were supported by a seed grant from the European Huntington Disease
Network (EHDN). TFO is currently supported by the DFG Center for Nanoscale
Microscopy and Molecular Physiology of the Brain. FH and PMD were also
supported by Project LISBOA-01-0145-FEDER-007660 (Cellular Structural and
Molecular Microbiology) funded by FEDER funds through COMPETE2020 -
Programa Operacional Competitividade e Internacionalização (POCI) and by national
funds through Fundação para a Ciência e Tecnologia (Refs. SFRH/BPD/63530/2009,
IF/00094/2013/CP1173/CT0005 and UID/CBQ/04612/2013). JBS was supported by
Fundação para a Ciência e a Tecnologia (Ref. SFRH/BD/85275/2012) and
FCT/MCTES (Ref. CBQ/04612/ICL3535, to FH and PMD). PMD, GMP and YPA
were also supported by Fundação para a Ciência e a Tecnologia (FCT-ANR/NEUNMC/0006/2013
and PTDC/NEU-NMC/2459/2014). FG thanks the Medical
Research Council (MRC) for funding that provided valuable infrastructure supporting
CitationHuman Molecular Genetics, 2017, ddx260
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics
VersionAM (Accepted Manuscript)
Published inHuman Molecular Genetics
PublisherOxford University Press (OUP)
NotesThe 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.