GRANULE NEURON PROLIFERATION IS REDUCED IN THE DEVELOPING CEREBELLUM OF THE NPC1-/- MOUSE, A MODEL OF HUMAN NIEMANN-PICK C1 DISEASE

Niemann Pick type C (NPC) disease is an neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, Npc1 and Npc2. A prominent feature of NPC1 disease in humans is massive loss of cerebellar Purkinje cells (PCs). Cerebellar granule neurons (GNs) have been little studied in mouse models of this disease, perhaps because their development takes place during the first three weeks of postnatal life, whereas signs of PC pathology occur in older mice. GNs are generated during the first two postnatal weeks from a progenitor layer named, external granule layer (EGL), where their proliferation is sustained by Shh and microglia-released growth factors that activate the Notch pathway. We have observed that postnatal development of cerebellar GNs is defective in Npc1-/- mice. Compared to age-matched wild-type, there is an accelerated disappearance of the EGL in these mice, which is due to a premature exit from the cell cycle of GN precursors. As a consequence, the siz