Abnormal BDNF signaling 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 protein residing in late endosomes/lysosomes that mediates the efflux of cholesterol. The massive loss of cerebellar Purkinje cells is the prominent feature of NPC1 disease. NPC1 patients develop ataxia and neurological manifestations including dementia. Studying the development of cerebellum in NPC1 mouse models, we observed a defective proliferation of granule neurons (GNs) that affects the size of all cerebellar lobules of NPC1-deficient mice. This GNs developmental defect occurs during the second postnatal week and is concomitant with abnormal generation and reception of Shh signaling at level of the primary cilium, an organelle implicated in various signaling pathways such as Sonic-hedgehog (Shh) and brain-derived neurotrophic-factor (BDNF). The activation of Shh pathway up-regulates BDNF, which in turn regulate the migration/differentiation of various neuronal and glial cells and the formation of synapses, playing an important role in the cytoarchitecture and connectivity within the cerebellar cortex. Our studies on Npc1nmf164 , a mouse hypomorphic mutant of NPC1 disease with slower disease progression, indicate that these mice display an abnormal BDNF signaling pathway in the developing cerebellum 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, thereby providing new targets for therapeutic intervention.