Ricerc@Sapienza

Niemann-Pick C1 (NPC1) disease is a lipid-storage disorder, characterized by cerebellar ataxia, unbalanced standing and neurological manifestations including dementia. Several NPC1 disease-causing mutations have been identified in Npc1 gene, encoding a protein residing in late endosomes/lysosomes that mediates the efflux of endocytosed cholesterol.
The massive loss of cerebellar Purkinje cells is the prominent feature of NPCD, resulting in progressive motor impairment. Studying the cerebellar development , we observed a defective proliferation of granule neurons that affects the size of all cerebellar lobules of Npc1-deficient mice. Moreover, defects in exocytosis/mobilization of synaptic vesicles (rich in cholesterol) as well as an imbalance between inhibitory/excitatory neurotransmission were observed in Npc1-deficient mice (Xu et al., 2010).
No effective cure is available for NPC1 disease; 2-hydroxypropyl-ß-cyclodextrin promoting the cholesterol movement from endosomes to cytosol, represents the major treatment, but has a limited penetration of blood-brain barrier, presents dose-dependent cytotoxicity and has a short half-life in bloodstream.
Since the damaging of intracellular cholesterol trafficking causes neuronal dyshomeostasis, this project is designed to identify alternative or supplementary drugs counteracting neuronal/glial dysfunction. Although these drugs would not rescue the defective intracellular trafficking of cholesterol, they are expected to ameliorate the clinical/cellular phenotypes, thus delaying the onset of motor and neurological deficits.
To this end, using Npc1 nmf164 mouse model that mimics the most frequent form of NPCD, I will investigate whether and how the administration of ceftriaxone and taurine, an antibiotic and amino-acid respectively:
- produce synergetic neuroprotective and antioxidant effects;
- improve cerebellar motor abilities;
- restore physiological processes of cerebellar functioning that are deeply affected in NPCD.