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PMID:21985783

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Citation

Keryer, G, Pineda, JR, Liot, G, Kim, J, Dietrich, P, Benstaali, C, Smith, K, Cordelières, FP, Spassky, N, Ferrante, RJ, Dragatsis, I and Saudou, F (2011) Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 121:4372-82

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.

Links

PubMed PMC3223861 Online version:10.1172/JCI57552

Keywords

Animals; Autoantigens/genetics; Autoantigens/metabolism; Brain/metabolism; Brain/pathology; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Centrosome/metabolism; Cilia/genetics; Cilia/metabolism; Cilia/pathology; Disease Models, Animal; Humans; Huntington Disease/genetics; Huntington Disease/metabolism; Huntington Disease/pathology; Mice; Mice, Knockout; Microtubules/metabolism; Mutant Proteins/genetics; Mutant Proteins/metabolism; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Peptides/genetics; Signal Transduction; Trinucleotide Repeat Expansion

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HAP1

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HD

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002586)

Seeded From UniProt

complete

HUMAN:HD

involved_in

GO:0045724: positive regulation of cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(CL:0000540)

Seeded From UniProt

complete

MOUSE:HD

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HD

involved_in

GO:1902857: positive regulation of non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HD

involved_in

GO:0071539: protein localization to centrosome

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2177755,MGI:MGI:2386570

P

Seeded From UniProt

complete

MOUSE:HD

involved_in

GO:0071539: protein localization to centrosome

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HD

involved_in

GO:1905505: positive regulation of motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2177755,MGI:MGI:2386570

P

Seeded From UniProt

complete

MOUSE:PCM1

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HD

involved_in

GO:0045724: positive regulation of cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

part_of:(CL:0000540)

Seeded From UniProt

complete

HUMAN:HD

part_of

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002586)

Seeded From UniProt

complete

MOUSE:HAP1

GO:0006917: induction of apoptosis

ECO:0000314:

P

fig. 6

complete
CACAO 2339

MOUSE:HAP1

GO:2000766: negative regulation of cytoplasmic translation

ECO:0000315:

P

fig. 4

complete
CACAO 2338

MOUSE:HAP1

GO:0048471: perinuclear region of cytoplasm

ECO:0000314:

C

Figure 1

complete
CACAO 2335

MOUSE:HAP1

GO:0005813: centrosome

ECO:0000314:

C

Figure1

complete
CACAO 2444

MOUSE:HAP1

GO:2000154: negative regulation of flagellar cell motility

ECO:0000314:

P

Figure 5: PolyQ-Htt accumulates PCM1 at centrosome and increases cilia length.

complete
CACAO 2455

MOUSE:HAP1

involved_in

GO:1902857: positive regulation of non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HAP1

acts_upstream_of_or_within

GO:1902857: positive regulation of non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000540)

Seeded From UniProt

complete

MOUSE:HAP1

part_of

GO:0005813: centrosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HAP1

part_of

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000540)

Seeded From UniProt

complete


See also

References

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