Lipids in neuronal physiology and pathology

Molecular and Cellular Neurobiology
Centro de Biología Molecular “Severo Ochoa” CSIC-UAM (CBMSO)

THE ROLE OF NPC1 PROTEIN IN SYNAPSES. IMPLICATIONS FOR NIEMANN PICK DISEASE TYPE C. Our laboratory is interested in understanding the role of lipids in neuronal physiology and pathology. To this aim we analyze mice in which the metabolism of lipids has been genetically impaired and mimic human diseases. This is the case of mice bearing a mutation in the gene encoding for the lipid transport protein Npc1. Mutations in Npc1 cause Niemann Pick disease type C (NPC). Most relevant among the symptoms of this deadly disease are cognitive and psychiatric alterations, which suggest impaired synaptic function as a key pathological event. However, little is known about the synaptic role of Npc1, which has been mainly related to cholesterol transport in the endolysosomal system. In this project we propose that Npc1 is responsible for the redistribution of cholesterol necessary in learning and memory processes. Npc1 deficiency will prevent cholesterol dynamism at synapses contributing to the cognitive and psychiatric problems in NPC patients.  To test this hypothesis we will analyze synaptosomes, slices and primary neuronal cultures from the hippocampus of Npc1 mutant mice. We will determine in these in vitro systems the levels and localization of lipids and proteins related to synaptic plasticity under different stimuli using Western blot, immunofluorescence and enzymatic assays. We hope to discover an unanticipated function of Npc1 with relevant implications in NPC pathology.

Biomolecules & Cell D.
Molecular Biomedicine