Abnormal BDNF signalling underscores defects of cerebellar development in a mouse model of Niemann-Pick type C1 disease

The Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. This causes, among others, a depletion of cholesterol in lipid rafts, likely impairing various signal transduction pathways. Therapies based on hydroxy-propyl-beta-cyclodextrins (HPBCD) administration represent at the moment the most promising approach. <br> Studying the early postnatal cerebellum development in a mouse model of NPC1 disease, we have observed: i) a reduced proliferation of granule neuron precursors; ii) a defective differentiation of glial cells, including Bergmann glia and oligodendrocytes; and, iii) abnormal expression/localization patterns of morphological and functional markers of both glutamatergic and GABAergic transmission.<br> Among signaling pathways controlling cerebellar development, Brain-Derived Neurotrophic Factor (BDNF) by binding the lipid raft-associated TrkB receptor exerts a crucial for proper proliferation and differentiation of various neuronal and glial cell, likely influencing the overall pattern of synaptic connectivity of the cerebellar cortex. <br> By pursuing the hypothesis that cholesterol depletion in lipid rafts may affect BDNF signalling pathway, we are characterizing expression patterns and activity of molecules of this pathway in NPC1 mouse models and wt littermates. <br> Exploiting immunohistochemistry and biochemical approaches, we have observed a downregulation of BDNF expression and activity in the cerebellar cortex of Npc1-deficient mice as early as at post-natal (PN) day 11. Interestingly, two subsequent injections of HPBCD, at PN4 and PN7 partly rescue this deficit. <br> Our findings pinpoint BDNF dysregulation, among others molecular mechanisms, as a possible candidate responsible for abnormal cerebellum morphogenesis, opening novel perspectives for NPC1 disease therapies