Shortened primary cilia length and altered Sonic hedgehog signaling in Niemann Pick C1 (NPC1) disease.

The Niemann Pick C1 (NPC1) disease is a neurodegenerative lysosomal disorder due to mutations in NPC1, a transmembrane protein related to Hedgehog receptor and involved in intracellular trafficking of cholesterol. Clinically NPC1, also called “juvenile Alzheimer’s”, presents severe cerebellar dysfunction and Purkinje cell (PC) degeneration and loss. We have recently found that the proliferation potential of cerebellar granule neuron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh signaling during the first two weeks of postnatal life. This finding prompted us to analyze the morphology and distribution of the primary cilium, a non-motile organelle, specialized for Shh signal transduction. Proper primary cilia structure and function are important for many types of cells, including neurons and glial cells, and defective cilia are responsible for several human genetic disorders. By immunohistochemistry and biochemical approaches, we have observed various defects in the Shh cascade (including Smootened, Patched and Glis) and a reduction in length and density of primary cilia. In particular Kif7, the cilia tip’s protein that regulates the activity of Smo/Glis, is upregulated in Npc1-/- mice, likely accounting for the shortening of primary cilia, observed in brain sections of Npc1-/- mice and cultured fibroblasts obtained from NPC patients. A single injection of hydroxypropyl-beta-cyclodextrin (HPBCD, the most promising therapy for NPC1 disease) at postnatal day 7 rescues this defects, restoring normal Shh signaling and primary cilia length/density. Our findings demonstrate that primary cilia function is impaired and that both Shh signal generation and reception are affected in Npc1-/- mice.