A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice

Neurobiol Dis. 2015 Aug;80:15-28. doi: 10.1016/j.nbd.2015.05.008. Epub 2015 May 16.

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by the toxic expansion of polyglutamine in the Huntingtin (HTT) protein. The pathomechanism is complex and not fully understood. Increasing evidence indicates that the loss of normal protein function also contributes to the pathogenesis, pointing out the importance of understanding the physiological roles of HTT. We provide evidence for a novel function of HTT in the cilium. HTT localizes in diverse types of cilia--including 9 + 0 non-motile sensory cilia of neurons and 9 + 2 motile multicilia of trachea and ependymal cells--which exert various functions during tissue development and homeostasis. In the photoreceptor cilium, HTT is present in all subciliary compartments from the base of the cilium and adjacent centriole to the tip of the axoneme. In HD mice, photoreceptor cilia are abnormally elongated, have hyperacetylated alpha-tubulin and show mislocalization of the intraflagellar transport proteins IFT57 and IFT88. As a consequence, intraflagellar transport function is perturbed and leads to aberrant accumulation of outer segment proteins in the photoreceptor cell bodies and disruption of outer segment integrity, all of which precede overt cell death. Strikingly, endogenous mouse HTT is strongly reduced in cilia and accumulates in photoreceptor cell bodies, suggesting that HTT loss function contributes to structural and functional defects of photoreceptor cilia in HD mouse. Our results indicate that cilia pathology participates in HD physiopathology and may represent a therapeutic target.

Keywords: Cilia; Huntingtin; Huntington's disease; Photoreceptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cilia / metabolism
  • Cilia / ultrastructure
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Microtubules / ultrastructure
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Photoreceptor Cells / metabolism*
  • Photoreceptor Cells / ultrastructure
  • Retina / metabolism
  • Retina / ultrastructure

Substances

  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins