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Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease
Guy Keryer, … , Ioannis Dragatsis, Frédéric Saudou
Guy Keryer, … , Ioannis Dragatsis, Frédéric Saudou
Published November 1, 2011
Citation Information: J Clin Invest. 2011;121(11):4372-4382. https://doi.org/10.1172/JCI57552.
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Categories: Research Article Neuroscience

Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease

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Abstract

Huntington disease (HD) is a devastating autosomal-dominant neurodegenerative disorder. It is caused by expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene that encodes a mutant HTT protein with a polyglutamine (polyQ) expansion at the amino terminus. Here, we demonstrate that WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1). Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation. In mice, deletion of Htt in ependymal cells led to PCM1 mislocalization, alteration of the cilia layer, and hydrocephalus. Pathogenic polyQ expansion led to centrosomal accumulation of PCM1 and abnormally long primary cilia in mouse striatal cells. PCM1 accumulation in ependymal cells was associated with longer cilia and disorganized cilia layers in a mouse model of HD and in HD patients. Longer cilia resulted in alteration of the cerebrospinal fluid flow. Thus, our data indicate that WT HTT is essential for protein trafficking to the centrosome and normal ciliogenesis. In HD, hypermorphic ciliogenesis may affect signaling and neuroblast migration so as to dysregulate brain homeostasis and exacerbate disease progression.

Authors

Guy Keryer, Jose R. Pineda, Géraldine Liot, Jinho Kim, Paula Dietrich, Caroline Benstaali, Karen Smith, Fabrice P. Cordelières, Nathalie Spassky, Robert J. Ferrante, Ioannis Dragatsis, Frédéric Saudou

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Figure 1

Htt associates with centrosome in a MT-dependent manner in mouse STHdh+/+ cells.

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Htt associates with centrosome in a MT-dependent manner in mouse STHdh+/...
(A) Immunostaining with anti-Htt (SE3619) and anti–γ-tubulin and (B) anti-ninein and anti-Htt (2B4) Abs. (C) Anti–γ-tubulin immunostaining of cells expressing pARIS-mCherry-Htt. (D) Anti–α-tubulin immunostaining of cells expressing GFP-Htt480-17Q. (E) Immunostaining of cells in control condition or after MT depolymerization (nocodazole) with anti-Htt (SE3619) and anti–α-tubulin Abs. (A–E) Cells were counterstained with DAPI. (F) Quantification of GFP-Htt480-17Q at centrosome in control or nocodazole conditions and after different washout times. n = 3; 750 cells per condition. *P < 0.05; ***P < 0.001. (G) Representative cells expressing mCherry-centrin1 and GFP-Htt480-17Q. The nocodazole-treated cell was in G2 phase (duplicated centrosomes). (H) Representative FRAP experiment of GFP-Htt480-17Q transfected cells in control or nocodazole conditions. (I) FRAP graph. Tendency curve was calculated for 4 bleached centrioles in control condition. Arrows in A, C–E, G, and H denote the centrosome. Scale bars: 5 μm; 1 μm (insets).
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