Cerebellar Brain-Derived Neurotrophic Factor (BDNF) defects in a mouse model of a lysosomal lipid storage disease

Lysosomal lipid storage diseases are characterized by abnormal amounts of lipid deposits in cells. When lysosomal function is impaired, degradation of intracellular material cannot proceed normally and toxic accumulation of substrates occurs. Niemann-Pick C1 (NPC1) disease is a lysosomal storage disorder due to abnormal function of NPC1, a transmembrane protein related to Hedgehog receptor and involved in intracellular trafficking of cholesterol. Clinically NPC1, also called “juvenile Alzheimer’s”, presents massive loss of cerebellar Purkinje cells, ataxia and neurological manifestations including dementia. Studying the development of cerebellum, we observed a defective proliferation of granule neurons that affects the size of all cerebellar lobules of NPC1-deficient mice. This defect occurs during the second postnatal week and is concomitant with abnormal generation/reception of Shh signaling at level of the primary cilium, an organelle implicated in various signaling pathways such as Shh and BDNF. The activation of Shh pathway up-regulates the BDNF expression, which in turn regulate synapse formation as well as connectivity within the cerebellar cortex. By immunohistochemistry/biochemical approaches, we have observed various defects in the cerebellar BDNF signaling of Npc1nmf164, a mouse hypomorphic mutant of NPC1 disease with slower disease progression. These mice display defects in almost all developmental stages analyzed and alterations in the fine structure and connectivity of mossy fibers. Mossy fiber axons represent one of the major inputs to the cerebellum and contain the highest concentration of BDNF in the CNS. These results pinpoint BDNF dysregulation as a possible candidate into the molecular pathogenesis of Niemann-Pick type C disease.