Niemann Pick type C (NPC1) disease is an autosomal recessive, neurodegenerative lysosomal storage disorder due to loss-of-function mutations in the NPC1 gene. We have characterized cerebellar cytoarchitecture in Npc1-/- mice, with particular reference to early postnatal development, an issue that has so far received little attention. In these mice, in fact, Purkinje cells (PC) degeneration and loss, the hallmark features of NPC disease at the cerebellar level, occur mostly between postnatal day (PN) 28 and PN40, becoming very pronounced at PN60. This “late PC phenotype” reasonably accounts for the present lack of information on granule neurons (GNs), the proliferation and differentiation of which are completed by PN 16.5. Based on the simple observation that the cerebellum of Npc1-/- adult mice is significantly smaller compared to that of wild-type mice, we have hypothesized that GN expansion is also affected by Npc1 loss of function. In fact, as GNs represent the most abundant cerebellar cell population, the overall cerebellar size and shape in the adult is likely to directly depend on their expansion. In agreement with this idea, we observed that Npc1 loss-of-function actually impairs cerebellar foliation by reducing lobule outgrowth. This feature apparently affected all lobules, suggesting a defect(s) in GN proliferation and/or Bergmann glia-mediated migration. Nearly a decade ago an efficacious effect of hydroxypropyl-beta-cyclodextrins (HPBCD) on slowing the neurodegeneration was demonstrated in the mouse model of Niemann-Pick C1. Thus, we investigated the effect of this drug on cerebellar development and found that a single HPBCD injection at PN7 fully re-establishes normal folia size and shape, further strengthening the need of Npc1 gene function for normal cerebellar foliation. Our findings on molecular/cellular mechanisms underlying GN expansion defects in Npc1-/- mice will be presented.
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|Titolo:||Niemann Pick C1 Gene Loss Of Function Impairs Cerebellar Foliation|
|Data di pubblicazione:||2012|
|Appartiene alla tipologia:||04b Atto di convegno in volume|