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.
Highlights
Huntington’s disease (HD) is characterized by the loss of medium spiny neurons in the striatum
Single N17 phosphomutants modulate huntingtin exon 1 (HTTex1) aggregation in human cells In order to investigate the contribution of each phosphorylatable residue within the N17 region (T3, S13 and S16) towards HTTex1 aggregation, we used the bimolecular fluorescence complementation (BiFC) system for the visualization of both oligomeric species and inclusion bodies of HTTex1 in living cells, which we have previously described [47,48,49]
Increasing evidence suggests that targeting phosphorylation events in the N17 domain of mutant HTT can influence the pathological function of the protein [28, 30, 36,37,38]
Summary
Huntington’s disease (HD) is characterized by the loss of medium spiny neurons in the striatum. The main histopathological hallmark of HD is the misfolding and subsequent intracellular aggregation of a mutant form of huntingtin (HTT) [1]. HTT is a very large protein (~350 kDa), but expression of exon 1 is sufficient to produce HDlike features in various cellular and animal models [2,3,4]. HTT exon 1 (HTTex1) contains a polyglutamine (polyQ) tract that, in normal conditions, is constituted by 6 to 35 glutamine residues. An expansion of the polyQ tract beyond 35 glutamines induces the misfolding and aggregation of mutant HTT and causes HD [5, 6]. Mutant HTT with longer polyQ expansions is more prone to aggregate, and leads to earlier onset of the disease [2, 7, 8]
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