title: Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease.
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.
authors.affiliation: Department of Psychology, Section of Neuroscience and Center for Research in Neurobiology 'Daniel Bovet', Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Canterini
authors.affiliation: Department of Psychology, Section of Neuroscience and Center for Research in Neurobiology 'Daniel Bovet', Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dragotto
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zampieri
authors.affiliation: Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology 'Charles Darwin' and Center for Research in Neurobiology 'Daniel Bovet', Sapienza University of Rome, Italy.
authors.forename: Maria Egle
authors.initials: ME
authors.lastname: De Stefano
authors.affiliation: Department of Psychology, Section of Neuroscience and Center for Research in Neurobiology 'Daniel Bovet', Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Mangia
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, AZ 85724-5073, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Erickson
authors.affiliation: Department of Psychology, Section of Neuroscience and Center for Research in Neurobiology 'Daniel Bovet', Sapienza University of Rome, 00185 Rome, Italy.|IRCCS Fondazione Santa Lucia, 00179 Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Fiorenza
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction; D047392:beta-Cyclodextrins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D053823:Hedgehog Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol