PATHOGENETIC MECHANISMS RESPONSIBLE FOR ALTERED DEVELOPMENTAL TRAJECTORIES IN NIEMANN PICK C DISEASE

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].