Impaired cerebellar granule neuron proliferation in Niemann-Pick C1 mice is corrected by a single hydroxyproplyl-betacyclodextrin injection

Niemann Pick type C (NPC) disease is an autosomal recessive, neurodegenerative lysosomal storage disorder due to the abnormal function of NPC1 or NPC2 proteins, involved in intracellular trafficking of cholesterol and other lipids. The deficiency of either protein leads to the accumulation of endocytosed unesterified cholesterol and other lipids, including spingomielin and gangliosides within lysosomes. The classic presentation of NPC disease is a child of either sex developing coordination problems, dysarthria and hepatosplenomegaly during early school-age years. A prominent feature of NPC1 disease in humans is the massive loss of cerebellar Purkinje cells (PCs). A similar feature is also observed in several mouse models of NPC1 disease, in which PC degeneration and loss initiates at PN28-PN40 and becomes very pronounced at PN60. Despite the huge interest for mechanisms underlying PC degeneration, the effect of Npc1 loss of function on overall cerebellar cortex morphology and size has mostly been disregarded so far. Studying the early postnatal development of cerebellar cortex in two mouse models of NPC1 disease, Npc1nih and Npc1nmf164, we have observed that the cerebellum of both adult mice is significantly smaller compared to that of wild-type, because of a defective proliferation of granule neurons (GNs) that apparently affects all cerebellar lobules. A single injection of hydroxy-propyl-beta-cyclodextrin (routinely used to remove cholesterol from, or present cholesterol to, cells in culture) at PN7 doubles the number of GNs in the cerebellum of Npc1nih and Npc1nmf164, re-establishing the normal size and shape of cerebellar lobules.