Ricerc@Sapienza

Niemann Pick type C (NPC) disease is an autosomal recessive, neurodegenerative
lysosomal storage disorder caused by the abnormal function of NPC1 or NPC2 (95%
and 5% of NPC patients, respectively), proteins involved in the intracellular
trafficking of endocytosed cholesterol and other lipids.
The accumulation/mislocalization of cholesterol, gangliosides, sphingolipids alters
signaling pathways, likely causing developmental defects. As an example, the
covalent cholesterol modification of Sonic hedgehog (Shh) and its downstream
effector, Smoothened, is relevant for gradient formation and downstream signaling
activation [1]. Hence, we have recently demonstrated that cholesterol dyshomeostasis
in NPC1 affects Shh-mediated activities, at the primary cilium. This impairs the
differentiation and functional maturation of neurons and glial cells, leading to
abnormal cerebellar morphogenesis [2]. Downstream from Shh, the dysregulation of
Brain-Derived Neurotrophic-Factor expression patterns appears to be responsible for
defective cell migration and synapse formation. In addition, our recent observations
indicate that the reduced cholesterol availability at the plasma membrane affects the
signaling of the endocannabinoid receptor CB1, in agreement with the influence that
cholesterol content in lipid rafts exerts on the portioning and internalization of this
receptor.
Hydroxypropyl-β-cyclodextrin (HPβCD), represents the major treatment currently
studied in both animal models and patients but it comes with several drawbacks. To
overcome these limitations we have recently validated a novel polymer prodrug
version of HPβCD, demonstrating that its enhanced pharmacokinetic/biodistribution
profiles and longer terminal half-life leads to a significant rescue of cerebellar
anomalies and neurobehavioral deficits of NPC1 mouse model, at a dose 5-fold lower
than the efficacious HPβCD dose [3].