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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 October 10, 2011
Citation Information: J Clin Invest. 2011;121(11):4372-4382. https://doi.org/10.1172/JCI57552.
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Research Article Article has an altmetric score of 6

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 2

Htt depletion mislocalizes PCM1 and impairs primary cilia formation in striatal cells.

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Htt depletion mislocalizes PCM1 and impairs primary cilia formation in s...
(A and B) Immunostaining of GFP-HAP1–transfected cells (A) for Htt (4C8) and γ-tubulin and (B) for PCM1. Arrows denote γ-tubulin staining. (C) Immunostaining of cells treated with scrambled RNA (sc-Htt) or siRNA targeting Htt (si-Htt) for Htt (SE3619) and γ-tubulin. (D) Immunoblotting of lysates from sc-Htt cells, si-Htt cells, and si-Htt cells expressing pARIS-Htt. (E) Immunostaining of sc-Htt or si-Htt cells with anti-Htt (4C8) and PCM1 Abs. (F) Immunostaining of cells transfected with sc-Htt, si-Htt, and si-Htt with pARIS-Htt for PCM1 and N-acetylated tubulin. (G) Quantification of primary cilia in cells as in F. n = 4; at least 1,227 cells per condition. ***P < 0.0001. (H) Immunostaining of cells transfected with GFP-sh-luciferase (GFP-sh-luc) and GFP-sh-Htt for N-acetylated tubulin. (I) Quantification of primary cilia in cells as in H. n = 2, at least 430 cells per condition. ***P = 0.001. (A–H) Cells were counterstained with DAPI. Scale bars: 5 μm; 1 μm (insets).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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