BDNF anomalies in Niemann Pick type C disease

Niemann-Pick C1 (NPC1) disease is a lysosomal lipid storage disorder due to abnormal function of NPC1, a transmembrane protein involved in intracellular trafficking of cholesterol. Clinically, NPC1 presents massive loss of cerebellar Purkinje cells, ataxia and neurological manifestations including dementia. We have previously demonstrated that the early postnatal cerebellar development is impaired in Npc1-deficient mice. The reduced cholesterol availability affects SHH signaling at level of the primary cilium that leads to a reduction of granule neuron precursors proliferative potential. The activation of Shh pathway up-regulates the BDNF expression, which in turn regulates synapse formation as well as connectivity within the cerebellar cortex. By immunohistochemistry/biochemical approaches, we have observed various defects in the cerebellar BDNF signaling in NPC1-hypomorphic mutant mice and alterations in the fine structure and connectivity of mossy fibers which represent one of the major source of BDNF in the cerebellum. These results pinpoint BDNF dysregulation as a possible candidate into the molecular pathogenesis of Niemann-Pick type C disease.