Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease

Sonia Canterini, Jessica Dragotto, Andrea Dardis, Stefania Zampieri, Maria Egle De Stefano, Franco Mangia, Robert P. Erickson, Maria Teresa Fiorenza

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder due to mutations in the NPC1 gene, encoding a transmembrane protein related to the Sonic hedgehog (Shh) receptor, Patched, and involved in intracellular trafficking of cholesterol. We have recently found that the proliferation of cerebellar granule neuron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh expression. This finding prompted us to analyze the formation of the primary cilium, a non-motile organelle that is specialized for Shh signal transduction and responsible, when defective, for several human genetic disorders. In this study, we show that the expression and subcellular localization of Shh effectors and ciliary proteins are severely disturbed in Npc1-deficient mice. The dysregulation of Shh signaling is associated with a shortening of the primary cilium length and with a reduction of the fraction of ciliated cells in Npc1-deficient mouse brains and the human fibroblasts of NPC1 patients. These defects are prevented by treatment with 2-hydroxypropyl-β-cyclodextrin, a promising therapy currently under clinical investigation. Our findings indicate that defective Shh signaling is responsible for abnormal morphogenesis of the cerebellum of Npc1-deficient mice and show, for the first time, that the formation of the primary cilium is altered in NPC1 disease.

Original languageEnglish
Pages (from-to)2277-2289
Number of pages13
JournalHuman Molecular Genetics
Volume26
Issue number12
DOIs
Publication statusPublished - Apr 3 2017

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Niemann-Pick Diseases
Hedgehogs
Cilia
Type C Niemann-Pick Disease
Inborn Genetic Diseases
Medical Genetics
Cyclodextrins
Morphogenesis
Organelles
Cerebellum
Signal Transduction
Proteins
Down-Regulation
Fibroblasts
Cholesterol
Neurons
Mutation
Brain
Therapeutics
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease. / Canterini, Sonia; Dragotto, Jessica; Dardis, Andrea; Zampieri, Stefania; De Stefano, Maria Egle; Mangia, Franco; Erickson, Robert P.; Fiorenza, Maria Teresa.

In: Human Molecular Genetics, Vol. 26, No. 12, 03.04.2017, p. 2277-2289.

Research output: Contribution to journalArticle

Canterini, S, Dragotto, J, Dardis, A, Zampieri, S, De Stefano, ME, Mangia, F, Erickson, RP & Fiorenza, MT 2017, 'Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease', Human Molecular Genetics, vol. 26, no. 12, pp. 2277-2289. https://doi.org/10.1093/hmg/ddx118
Canterini S, Dragotto J, Dardis A, Zampieri S, De Stefano ME, Mangia F et al. Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease. Human Molecular Genetics. 2017 Apr 3;26(12):2277-2289. https://doi.org/10.1093/hmg/ddx118
Canterini, Sonia ; Dragotto, Jessica ; Dardis, Andrea ; Zampieri, Stefania ; De Stefano, Maria Egle ; Mangia, Franco ; Erickson, Robert P. ; Fiorenza, Maria Teresa. / Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 12. pp. 2277-2289.
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