NPC brains undergo a massive loss of neurons, astrogliosis, and progressive loss of myelin, but the contribution of each brain cell type to the pathology is not known. I am addressing this question by restoring a tagged-Npc1 protein to different neurons, astrocytes, and oligodendrocytes in the Npc1-/- mouse model background. I am using a technology that allows cell-specific and temporal regulation of Npc1-Tag expression. With these new mice I am delineating the sequence of events of the disease and determine when in the progression of the disease the pathology can be rescued. In the second part of my project I plan to investigate cellular and molecular mechanisms of NPC protein function. Npc1 is a membrane protein found in a subset of endosomes and lysosomes.Niemann-Pick C disease is a lysosomal storage disorder caused by genetic defects in the NPC1 gene. As a result of loss of NPC1 function transport of cellular organelles is perturbed and large quantities of intracellular cholesterol accumulate. These defects lead predominantly to liver and brain degeneration. To determine the relevance of different cell types to the etiology and pathology of the disease, we have engineered mice in which production of a tagged NPC1 protein can be spatially and temporally controlled.
Currently, I’m doing a second postdoc, now at the Weizmann Institute of Science, in Israel. I’m still working on Lysosomal Storage Disorders, but from a diferent prospective. I’m looking for modifiers genes of disease progression. I have a strong interest in identifying genetic factors that modify Gaucher disease (GD) progression. GD is caused by the defective activity of lysosomal acid-alpha-glucosidase (glucocerebrosidase, GBA), resulting in accumulation of the glycosphingolipid, glucosylceramide (GlcCer). The disease can be divided into 3 major subtypes: type 1 present hepatospleenomegaly, types 2 and 3 result in severe neurological disorders in patients. For most part of GD patient’s a defined correlation between genotype and phenotype does not exist. Indeed, the same mutation leads to complete different clinical manifestations, indicating that there are “modifiers of disease progression”. Little is known about the down-stream biochemical changes that occur upon GlcCer accumulation that result in cell and tissue dysfunction in different types of GD. I plan to identify the genetic and biochemical factors that regulate the severity of disease progression, in order to design personalized therapies, customized for each patient.