Altered development of cerebellar granule neurons in a mouse model of Niemann-Pick type C1 disease

Niemann-Pick type C1 disease (NPCD), also called “Juvenile Alzheimer’s Disease”, is a lysosomal cholesterol storage disorder due to mutations in the NPC1 gene, presenting visceral/neurological impairments associated with cognitive decline. NPC1 neurodegeneration is characterized by the presence of amyloid-β deposition and tau aggregations, alike to Alzheimer's disease. Unfortunately, the molecular mechanisms that cause neurodegeneration in this disease are currently unknown. Studying the cerebellar development in Npc1 mutant mice, we observed a defective proliferation of granule neurons (GNs)1, concomitant with the dysregulation of Sonic Hedgehog (Shh) and Brain Derived Neurotrophic factor (BDNF) expression, that affects the size of cerebellar lobules2 . Aims: In light of the relevance of BDNF in a wide range of neurophysiological processes, as neuronal migration, differentiation and degeneration3, we analyzed BDNF-TrkB signaling during the first weeks of postnatal life, in a milder mouse model, Npc1nmf164, harboring a missense mutation in a region where a high proportion of human mutations are found and associated with a slower disease progression. Materials and Methods: In order to study the expression and localization of BDNF/TrkB, we performed Western Blot and Immunofluorescence analyses in cerebellar samples of wt and Npc1nmf164mice. Cerebellar neuron responsiveness to BDNF was investigated by chemotaxis assay in in vitro culture, while neuronal differentiation was studied by detailed dendritic branching analysis of Golgi-stained GNs. Results: We observed an altered expression/localization of BDNF and its receptor TrkB, at the very early stages of cerebellar development. Furthermore, purified GNs from Npc1nmf164 mice, in the presence of exogenous BDNF, exhibit a reduced chemotaxis response, dependent on altered TrkB receptor trafficking. Using Golgi staining, we observed that mature GNs present an abnormal dendritic morphology. Discussion These data raising the possibility that morpho-functional anomalies in granule neurons largely anticipate the overt manifestation of symptoms in adult NPC1 patients. Our focus on very early morphological/ biochemical defects, which precede neurodegeneration in adults, is relevant for identifying predictive markers, useful for NPC1 disease treatment. Thus, given the potential of BDNF to protect synapses against various toxic insults, manipulation of BDNF could represent a valid therapeutic approach for a variety of neurological disorders, including NPC1 disease. Conclusions: Here, we propose that an altered BDNF signaling is a part of complex cerebellar deficits, which may be predictive of symptomatic events in NPCD, as well as the progressive neurodegeneration of Purkinje cells in adulthood.