title: Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease.
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: Institut Curie, Orsay, France.
authors: Guy
authors: G
authors: Keryer
authors: Jose R
authors: JR
authors: Pineda
authors: Géraldine
authors: G
authors: Liot
authors: Jinho
authors: J
authors: Kim
authors: Paula
authors: P
authors: Dietrich
authors: Caroline
authors: C
authors: Benstaali
authors: Karen
authors: K
authors: Smith
authors: Fabrice P
authors: FP
authors: Cordelières
authors: Nathalie
authors: N
authors: Spassky
authors: Robert J
authors: RJ
authors: Ferrante
authors: Ioannis
authors: I
authors: Dragatsis
authors: Frédéric
authors: F
authors: Saudou
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D015398:Signal Transduction; D019680:Trinucleotide Repeat Expansion
chemical_list: D001324:Autoantigens; D018797:Cell Cycle Proteins; C096896:HAP1 protein, human; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C086074:PCM1 protein, human; D010455:Peptides; C097188:polyglutamine