Niemann-Pick type C1 disease (NPC1) is a neurodegenerative disorder characterized by the accumulation of cholesterol in late endosomal/lysosomal compartments, due to the abnormal function of NPC1 protein involved in the intracellular cholesterol transport. The main feature of NPC1 disease is the progressive neuronal loss, especially of Purkinje cells (PCs), which leads to cerebellar ataxia. Studies performed by the research group in which I¿m currently working as a Ph.D student, showed a defective proliferation of granule neurons during the second postnatal week in Npc1 mutant mice, compromising cerebellar cytoarchitecture in the adulthood. We have shown that, in Npc1-deficient mice, the altered proliferation and maturation of GNs is due to a reduction of Sonic Hedgehog and Brain-derived neurotrophic factor (BDNF), at very early stages of cerebellar development.
Given the key role of Brain-derived neurotrophic factor on synaptic growth, transmission and plasticity, I propose to investigate whether an overall reduction in BDNF levels, associated with its different localization along the cerebellar cortex layers, could deregulate expression and localization of specific synaptic proteins and induce synaptic dysfunction, a common denominator of many neurodegenerative disorders. To this end, I will use the hypomorphic mouse model, Npc1 nmf164, that mimics the most frequent form of human disease.
Since a reduction in BDNF levels is also associated with autism spectrum disorders, this project aims to investigate similar autistic behaviors in Npc1 nmf164 mice, correlating biochemical aspects with functional and behavioural defects.
With respect to NPC1 disease, the novelty and originality of this project is to shift the focus from neuropathological and neurodegenerative features, present in adulthood patients, to synaptic dysfunction already present in the very early stages of postnatal development. Since synapse dysfunction and loss, unlike neuronal loss, are reversible processes, the present study aims to gain deeper insight on how to mimic or engage endogenous neuroprotective mechanisms directed at recovering the synaptic homeostasis.
In addition, BDNF and cerebellar abnormalities in autism spectrum disorders are associated with deficits in cognitive and motor behavior and social reward; all these aspects are, however, in common with NPC1 disease. For this reason, we believe that characterizing the NPC1 disease may contribute to future cellular and molecular mechanism studies underlying autism pathogenesis.
The most promising therapy for NPC1 disease is the treatment with HPBCD, which has been shown to fully rescue cerebellar anomalies when administered to early Npc1-deficient mouse mice. However, the poor/lack of HPBCD ability to penetrate the brain blood barrier (BBB) dramatically limits the efficacy of this drug on neurological impairments. In this way, given the potentiality of BDNF to protect/repair synapse against various toxic insults and given that synapse loss is reversible and predictive of disease progression, targeting mechanisms that stabilize, protect, repair and regenerate synapse would enable clinical intervention at both early and late stages of the disease. Thus, manipulating BDNF expression and pathways could represent a viable treatment approach to a variety of neurological disorders, including NPC1 disease. In light of this, I expect that the results obtained in this study will help to identify the molecular bases of NPC1 disease to contribute to the identification of novel tools for the diagnosis along with novel therapeutic approaches.