Postnatal BDNF-mediated cerebellar granule cell development is impaired in a mouse model of Niemann-Pick type C1 disease

Niemann-Pick type C1 disease (NPCD) is a lysosomal storage disorder due to mutations in NPC1, a lysosomal protein related to the Sonic Hedgehog (Shh) receptor and involved in the intracellular trafficking of cholesterol. Clinically NPCD, also called "juvenile Alzheimer's," exhibits systemic and neurological symptoms, including severe cerebellar ataxia and Purkinje cell (PC) degeneration. In the cerebellum of Npc1 mutant mice, we found a significant downregulation of the Shh signaling pathway leading to a defective proliferation of cerebellar granule (CG) precursors, with consequent reduction of overall cerebellar size. Aims: Since Shh promotes Brain Derived Neurotrophic Factor (BDNF) expression, we wondered if BDNF-TrkB signaling pathway was altered in a hypomorphic mouse model, Npc1nmf164, harboring a point mutation in the Npc1 gene and representing a slow progression disease model. Methods and Results: By immunohistochemical , biochemical approaches and primary in vitro culture of GCs, we observed an altered expression and localization of BDNF (including its precursor form, proBDNF, and TrkB/ p75 receptors) at the very early stages of cerebellar development. In particular, purified GCs from Npc1nmf164 mice, in the presence of exogenous BDNF, exhibit a reduced chemotaxis response, dependent on altered activation and localization of TrkB receptor. We demonstrate that defective BDNF signaling during cerebellar postnatal development leads to abnormal maturation and differentiation of GCs and glomerular rosette, a multi-synaptic structure formed between a mossy fiber axon and dendrites of numerous cerebellar GCs Conclusions:. Here, we propose that an altered BDNF signaling expression and localization is a part of complex cerebellar deficits, which may be predictive of symptomatic events in NPCD. This suggests that the ataxia and selective vulnerability of PCs, observed in mice and humans, are a consequence of dysregulated developmental events.