Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease.
J. Clin. Invest.. 2011-11-01; 121(11): 4372-4382
DOI: 10.1172/jci57552
Lire sur PubMed
1. J Clin Invest. 2011 Nov;121(11):4372-82. doi: 10.1172/JCI57552. Epub 2011 Oct 10.
Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in
Huntington disease.
Keryer G(1), Pineda JR, Liot G, Kim J, Dietrich P, Benstaali C, Smith K,
Cordelières FP, Spassky N, Ferrante RJ, Dragatsis I, Saudou F.
Author information:
(1)Institut Curie, Orsay, France.
Comment in
J Clin Invest. 2011 Nov;121(11):4237-41.
Expert Rev Proteomics. 2012;9(1):17-9.
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.
DOI: 10.1172/JCI57552
PMCID: PMC3223861
PMID: 21985783 [Indexed for MEDLINE]