Ricerc@Sapienza

Niemann Pick type C (NPC) disease is an autosomal recessive, neurodegenerative lysosomal storage disorder with a highly variable phenotype. The disease is due to the abnormal function of NPC1 or NPC2 proteins, which are involved in the intracellular trafficking of cholesterol and other lipids. Loss-of-function mutations in the NPC1 gene, which encodes a protein essential for mobilizing cholesterol from the endo-lysosomal compartment, disrupt intracellular lipid trafficking in 95% of NPC patients, whereas the remaining 5% have mutations in the NPC2 gene. 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 days of age. Recently, studies performed by the research group I¿m presently working as PhD student have shown that the early postnatal cerebellar development is impaired in Npc1-deficient mice. The reduced cholesterol availability affects cerebellar development by reducing proliferative potential of Npc1-/- mice cerebellar granule neuron (GN) precursors and compromising cerebellar morphogenesis. In particular, we have observed: 1) an overall reduction of cerebellar lobule size, morphological and functional anomalies of Bergmann glia as early as PN15 in Npc1-/-mice; a reduction of both glutamatergic and GABAergic inputs that PCs receive by climbing/parallel fibers and basket/stellate interneurons, respectively; 3) an impairment of oligodendrocyte differentiation. All together, these findings indicate that abnormal development of glial and neuronal cells of Npc1-/- mice likely contributes to PCs degeneration. In light of these findings, this project is aimed at analyzing the contribution of the abnormal development of neuronal and glial cells to NPC neuropathology, with particular reference to the neurodegeneration and loss of Purkinje cells.