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

Guy Keryer1, Jose R Pineda, Géraldine Liot

  • 1Institut Curie, Orsay, France.

The Journal of Clinical Investigation
|October 12, 2011
PubMed

Insights

Wild-type huntingtin (HTT) protein is vital for normal primary cilia formation by regulating protein transport. In Huntington disease (HD), altered HTT leads to abnormal cilia growth, potentially worsening brain dysfunction.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder.
  • HD results from a CAG repeat expansion in the huntingtin (HTT) gene, producing a mutant HTT protein with a polyglutamine (polyQ) expansion.
  • The precise function of wild-type (WT) HTT in cellular processes remains under investigation.

Purpose of the Study:

  • To investigate the role of WT HTT in ciliogenesis.
  • To determine how mutant HTT affects primary cilia formation and function in Huntington disease.

Main Methods:

  • Utilized mouse cell models and mouse models of HD.
  • Examined the interaction between HTT, huntingtin-associated protein 1 (HAP1), and pericentriolar material 1 protein (PCM1).
  • Assessed protein trafficking, ciliogenesis, cilia length, and cerebrospinal fluid flow.

Main Results:

  • WT HTT interacts with HAP1 and PCM1, regulating PCM1 retrograde trafficking and primary cilia formation.
  • Loss of Htt in mouse cells impaired PCM1 trafficking and reduced cilia formation.
  • In HD models and patients, pathogenic polyQ expansion led to PCM1 accumulation, abnormally long cilia, and altered cerebrospinal fluid flow.

Conclusions:

  • WT HTT is essential for centrosomal protein trafficking and normal ciliogenesis.
  • Aberrant ciliogenesis in HD may contribute to neurodevelopmental dysregulation and disease progression.
  • Targeting ciliogenesis could offer new therapeutic strategies for Huntington disease.

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